ALBERT

Description: Adoptive immunotherapy with transplant donor derived virus specific T cells is an effective strategy for the treatment of CMV viremia and disease arising after an allogeneic hematopoietic stem cell (HSCT). This approach is not readily applicable if the donor is seronegative or not available to provide lymphocytes for in vitro expansion for CMV specific cytotoxic T lymphocytes (CMV-CTL) lines or if the CMV CTL lines derived from non-identical donors are restricted by non-shared HLA alleles. We and others have previously presented results indicating that treatment with in vitro expanded CMV-CTLs derived from an HLA partially matched third party donors can effectively treat CMV infections in the post-transplant setting. However, the patient population most likely to benefit from this approach has not been well defined. Patients at especially high risk of succumbing to CMV infection include those who acquire resistance to antiviral therapy. We now present results of treatment with banked off-the-shelf third party CMVpp65 specific CTLs in patients with genetically defined mutations in the UL54 DNA polymerase and UL97 kinase CMV genes predicting resistance to antiviral agents. Fifteen recipients of HSCT with mutations defined prior to the start of cell therapy were treated. All 15 had mutations associated with resistance to ganciclovir. Overall 5 had resistance to ganciclovir, foscarnet and cidofovir, 5 had resistance to ganciclovir and foscarnet, one had resistance to ganciclovir and cidofovir and 4 had resistance to ganciclovir alone. Third party CMV-CTLs were selected on the basis of HLA matching at high resolution at a minimum of 2/8 recipient alleles and HLA restriction of the T cells by one or more HLA alleles present in the patient. CMV-CTLS were selected from a bank of 132 lines generated under GMP conditions from normal HSCT donors specifically consented for use of their T cells in patients other than the designated transplant recipient. These 15 patients had a median age of 60.5 (7.4-70.1) years and started therapy with CMV-CTLs a median of 157 (70-564) days after reactivation of CMV. Four of these patients had CMV disease while 11 were treated for viremia alone. Prior therapy in this cohort included foscarnet (N=15) ganciclovir and/or valganciclovir (N=14) and cidofovir and/or brincidofovir (N=9). Each cycle of CMV-CTLs consisted of 3 weekly infusions of 1x106 T-cells/kg/infusion. These 15 patients received a median of 2 (1-3) cycles of CMV-CTLs. CMV-CTLs were well tolerated and there were limited toxicities. Six patients experienced AEs of which one grade 3 and one grade 4 AE were deemed possibly related to infusions with CMV-CTLs. Overall 11/15 (73.3%) patients responded to CMV-CTL therapy including 2 patients with disease with 6 CRs and 5 PRs. Overall survival at 6 months in the 11 responders and 4 non-responders was 72.7% and 25.0% respectively. Within the 6 month follow-up one of the 11 responding patients died of CMV while 3 of the 4 non-responding patients died of CMV. These results indicate that third party donor derived "off-the-shelf" CMV-CTLs can effectively treat CMV viremia or disease in patients not responding to antiviral therapy with demonstrated genetic resistance to antiviral agents. Figure 1. Figure 1. Disclosures Doubrovina: Atara Biotherapeutics: Consultancy, Research Funding. Hasan:Atara Biotherapeutics: Consultancy, Research Funding. Koehne:Atara Biotherapeutics: Consultancy.

Description: Introduction: Hepatic veno-occlusive disease (VOD) is a serious complication of hematopoietic stem cell transplantation (HSCT) and, in severe cases, is associated with multi-organ failure and mortality rates exceeding 80% (Coppell et al. Biol Blood Marrow Transplant, 2010, p157-168). In the US there are currently no FDA-approved treatments for severe VOD. Defibrotide, an oligonucleotide with a mechanism of action that encompasses both restoration of the thrombo-fibrinolytic balance and endothelial cell protection, has recently been approved for the treatment of severe VOD following HSCT in the EU. The data presented are based on the primary and secondary endpoint analyses provided to the European Medicines Agency (EMA) that formed the basis of the defibrotide approval in the EU. Methods: A pivotal phase 3 study examined the efficacy and safety of defibrotide 25 mg/kg/day in patients with severe VOD (n=102) compared to historical controls (n=32) (Defibrotide Summary of Product Characteristics. Villa Guardia, Italy: Gentium SpA; 2013). The study’s primary endpoint was complete response (CR) (in terms of improvements in total bilirubin and resolution of multi-organ failure measured by renal and/or pulmonary dysfunction) by 100 days post-HSCT; secondary endpoints included survival 100 days and 180 days post-HSCT. We calculated the number needed to treat (NNT) with defibrotide to achieve one complete response and the NNT to prevent one death 100 days post-HSCT in patients with severe VOD compared to historical controls who did not receive defibrotide in order to evaluate how defibrotide compared to other novel and efficacious agents used for rare conditions in hemato-oncology. NNT is calculated as the reciprocal of the absolute risk reduction (1/ARR), where ARR is equal to the control minus experimental event rates (Laupacis et al, New Engl J Med, 1988, p1728-1733). Results: In the defibrotide trial, complete response by day 100 was achieved in 23.5% of the defibrotide-treated patients and 9.4% of the historical controls (P=0.013), which equated to an NNT of 7 (1/(0.235-0.094)) to achieve one complete response 100 days post-HSCT. Day 100 survival was 38.2% in the defibrotide group and 25.0% in the historical control group (P=0.034) (Defibrotide Summary of Product Characteristics. Villa Guardia, Italy: Gentium SpA; 2013). Therefore, the NNT to prevent one death in this study was 8 (1/(0.382-0.25)). To compare the NNTs in this analysis with those in other studies, a literature search was conducted, identifying a selected number of pediatric oncology clinical trials published within the previous 10 years each of which reported 5-year EFS rates (Sorrell et al, Cancer, 2012, p4806-4814; La et al, Int J Radiat Oncol Biol Phys, 2011, p1151-1157; Chou et al, Cancer, 2009, p5339-5348; Lange et al, Blood, 2008, p1044-1053; MacDonald et al, Cancer, 2005, p2862-2871). NNTs calculated from that review ranged from 5 to 50. Conclusion: The results of this pivotal Phase 3 trial showed improved complete response and survival in defibrotide-treated patients compared to historical controls who did not receive defibrotide for the treatment of severe VOD. The number needed to treat to achieve this benefit proved either comparable or lower than the NNT obtained for other widely-accepted and approved therapeutic medical interventions in hemato-oncology. Support: Jazz Pharmaceuticals Off-Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease in the United States. Disclosures Richardson: Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals Inc.: Research Funding. Off Label Use: Defibrotide is an investigational treatment for veno-occlusive disease in the United States.. Martin:EUSA Pharma - an international division of Jazz Pharmaceuticals: Employment; Jazz Pharmaceuticals: Equity Ownership. Hannah:Jazz Pharmaceuticals: Consultancy. Villa:Jazz Pharmaceuticals: Employment, Equity Ownership.

Description: Twenty five patients have been enrolled on this trial to date. There were 14 males and 11 females aged 0.6–54 years. Patients’ diagnoses and stage included: NHL in CR2 or refractory (n=2), AML (n=7), including 5 pts with secondary AML, ALL 〉 CR3 (n=4), CML in CP2 (N=1) and high risk MDS (n=11) including 5 pts with secondary MDS. Eight pts had a matched related donor, 14 pts an unrelated donor and 3 pts a mismatched related donor. Cytoreduction consisted of busulfan (Bu) (0.8–1 mg/Kg/dose x 10 doses), melphalan (Mel) (70 mg/Kg/day x 2) and fludarabine (Flu) (25 mg/m2/day x 5). Graft rejection prophylaxis included rabbit ATG (Thymoglobulin) (2.5 mg/Kg/day x 2). Four pts tolerated only one of two doses of the ATG, 2 pts received equine ATG and one pt Alemtuzumab. Twenty one pts received G-CSF mobilized peripheral blood stem cell transplants that were T-cell depleted by CD34 selection and E-rosetting while the other four pts received Soybean agglutinin E-rosette depleted marrow grafts. Cell doses were 1.3–20.5 x 106 CD34 cells/Kg. and 0 -100 x 103 CD3 cells/Kg. Engraftment occurred in 24 pts. One pt suffered a graft failure; This pt had initial low busulfan levels, and received bone marrow derived stem cells with a low cell dose from a 5/6 HLA-matched unrelated donor. Acute graft-versus-host disease occurred in four pts: grade 1 (n=2) and grade 2 (n=2) and no pts developed any grade 3-4 severe GvHD. Two patients were diagnosed with chronic GvHD: localized (n=1) and extensive (n=1). Two patients developed sepsis early post BMT, with secondary multi organ failure and early mortality, while for the rest of the patients, regimen-related toxicity was acceptable. Relapse occurred in 9 pts. Mortality included 7 pts from relapse, two pts from sepsis and multi-organ failure, 3 pts from infections, and one pt from unknown causes. The overall survival (OS) and disease-free survival (DFS) at 2 yrs for the entire patient cohort were respectively 44% and 42 %; The DFS was 50% for patients with secondary MDS or AML. In summary, the cytoreduction with Bu Mel and Flu allowed consistent engraftment of T-cell depleted grafts and was associated with acceptable outcome for patients with secondary MDS or AML.

Description: Background: Severe hepatic veno-occlusive disease (VOD, also referred to as sinusoidal obstruction syndrome) with associated multi-organ failure (MOF) is a life-threatening complication of hematopoietic stem cell transplant (HSCT) and has an associated mortality rate 〉80%. Defibrotide has been shown to have a protective effect on injured endothelium and to restore the thrombo-fibrinolytic balance. In severe VOD, defibrotide has improved complete response (CR) rates and survival at Day +100 post HSCT compared with historical controls, and has also been shown to have a favorable safety profile. In the EU, defibrotide is now approved for the treatment of severe hepatic VOD in HSCT therapy. It is indicated in adults, adolescents, children, and infants 〉1 month of age. In the USA, there are currently no approved therapies for this complication; however, defibrotide has been made available since 2007 through an expanded access protocol directed treatment IND (T-IND). The aim of the T-IND is to gather additional data on safety and efficacy of defibrotide in a broader patient population, including those with severe VOD/MOF post HSCT, non-severe VOD post HSCT, and VOD following chemotherapy in the non-HSCT setting. This is the largest prospective evaluation of defibrotide for the treatment of VOD. Here we provide an update on the safety of defibrotide from this ongoing study. Methods: The original T-IND protocol required patients to have a diagnosis of VOD by Baltimore criteria (total bilirubin ≥2.0 mg/dL with ≥2 of the following: hepatomegaly, ascites, or 5% weight gain) with MOF (either renal and/or pulmonary failure) following HSCT; the study was amended to allow inclusion of patients with non-severe VOD (defined as no MOF) occurring either post-HSCT or post-chemotherapy. Key exclusion criteria include clinically significant bleeding or the need for 〉1 vasopressor. Defibrotide was given as a 2-hour infusion at 6.25 mg/kg IV every 6 hours (25 mg/kg/d) with a recommended minimum treatment duration of 21 days. Results: The current interim safety analysis is based on 612 patients enrolled between December 2007 and December 2013 (including 99 in 2013) for whom safety data is available and who received ≥1 dose of defibrotide. Across the USA, over the course of the study approximately 86 centers were active to enroll patients. Median patient age was 12 years (range 18 to 65 years, and 1.2% aged 〉65 years. Patients were primarily male (55.8%) and predominantly white (65.6%). Overall, 454 patients (74.2%) reported ≥1 treatment emergent adverse events (AEs). Of these, 138 patients (22.5%) had AEs that investigators assessed as related (possibly, probably, or definitely) to study medication. Related AEs in 〉2.0% were pulmonary hemorrhage (4.7%), gastrointestinal hemorrhage (3.6%), epistaxis (3.1%), and hypotension (2.8%). Serious AEs (SAEs) were reported by 368 patients (60.1%). The majority of SAEs were assessed as not related to study treatment; 82 patients (13.4%) had an SAE at least possibly related to study treatment, most commonly pulmonary hemorrhage (3.9%) and gastrointestinal hemorrhage (2.9%). AEs leading to death occurred in 254 patients (41.5%); these AEs were deemed by the investigators to be possibly related to study medication in only 17 patients (2.8%). Previously reported efficacy data at D +100 in 425 patients evaluable for outcome have shown survival of 55% (by Kaplan-Meier estimate) for patients following HSCT, and survival of 62% (by Kaplan-Meier estimate) in 45 patients following chemotherapy (without HSCT), respectively. Conclusions: Defibrotide therapy in patients with VOD was generally well tolerated in this population, with manageable toxicity, and promising results seen in terms of response and survival. Safety results from prior studies, which have also been associated with a low incidence of defibrotide-associated toxicities, have proven very consistent with the favorable tolerability profile seen in this largest experience to date. Enrollment to the T-IND study continues; updated results will be presented at the meeting. Support:Jazz Pharmaceuticals Off-Label Use Defibrotide is an investigational treatment for hepatic veno-occlusive disease in the United States. Disclosures Richardson: Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals Inc.: Research Funding. Off Label Use: Defibrotide is an investigational treatment for veno-occlusive disease in the United States.. Antin:Dana-Farber Cancer Institute: Employment; Tempera: Consultancy; Enlivex: Consultancy. Lehmann:Dana Farber/Boston Children's Hospital: Employment. Bandiera:Gentium S.p.A.: Employment. Hume:Jazz Pharmaceuticals Inc.: Employment. Hannah:Jazz Pharmaceuticals: Consultancy. Nejadnik:Jazz Pharmaceuticals: Employment. Study Group:Gentium S.p.A.: Employment.

Description: Abstract 1942 BACKGROUND: Poor graft function without immune rejection, defined as persistent cytopenias with a hypocellular marrow and full donor chimerism, is a life-threatening complication after allogeneic HSCT. Treatment options include supportive therapy with transfusions and growth factors, vs administration of additional HSCs from the same donor without any conditioning (stem cell boost). The use of unmanipulated boosts increases the risk of development or worsening of GvHD by virtue of infusing mature T cells. The aim of this retrospective study was to evaluate the efficacy and safety of TCD boosts in patients with PGF. PATIENT AND METHODS: Between January 1992 and December 2007, 35 patients from a single center with PGF following either an unmanipulated (10) or a TCD (25) allogeneic HCST received a TCD HSC boost collected from the original donor. T cells were removed ex-vivo from marrow grafts with soybean lectin agglutinin and sheep red blood cells (sRBC) rosetting and from peripheral blood stem cell grafts by positive selection with a CD34 antibody (Isolex) followed by sRBC rosetting. HSC donors were matched related (21), mismatched related (5) and unrelated (9). Indication for first transplant included: aplastic anemia (2), non-Hodgkin's lymphoma (5) and myeloid malignancies (28). The preparative regimen was myeloablative for all recipients of unmanipulated grafts and for 22 of 25 recipients of TCD grafts. With the exception of one patient, the cell dose as measured by total nucleated cell dose/kg or CD34 cells/kg was adequate. Following the initial transplant, all patients had partial or complete recovery of blood counts and full donor chimerism documented by karyotype, FISH analysis or DNA polymorphism. The median time from first transplant to the diagnosis of PGF was 4.5 months (0.72-90.7). Etiologies of PGF included: viral infection and anti-virals (10), bacterial sepsis (3), Mycobacterial infection (4), low cell dose (1), GvHD 12, and idiopathic (5). None of the patients had evidence of relapse or progression of their underlying disease. All patients received a TCD boost from the original donor; with 21 patients receiving bone marrow and 14 receiving PB HSC. RESULTS: Seven patients died before day 21 post boost and were not evaluable for blood count improvement. Improvement (PLT〉50,000/μL, ANC〉500/μL) occurred in 20 of the 28 evaluable patients (71.4 %) at a median time of 3.2 months; 17 of them (60.7%) had a more substantial improvement (PLT ≥100,000/μL and ANC31000/μL) at a median of 8.81 months. TCD boost infusions were well tolerated with no significant adverse events. Also, no new onset GvHD occurred after TCD boosts; although two patients with preexisting GvHD flared. The median survival for all patients following TCD boosts was 21.47 months (range: 1.84–208.45). The 2-year and 5-year survivals were 48.6% and 37.1% respectively. The 2-year survival for patients who had improvement of their counts was 90% and for those who remained pancytopenic despite the boost was 18%. The 2-year survival according to etiology was 52.9% for the infection group, 50% for the idiopathic and low cell dose, and 33.3% for the GvHD group. Patients were also analyzed according to their medical condition prior to receiving the boost and were separated into four groups based on organ function (serum creatinine ≥ 2; total bilirubin ≥ 2; need for mechanical ventilation) and infection status. Group A: outpatient with no infection and no organ dysfunction (9); group B: hospitalized but afebrile with no infection or organ dysfunction (7); group C: febrile or documented infection but preserved organ function (8); group D: organ dysfunction with or without a concurrent infection (11). The 2-year survival for each group was 55.6%, 85.7%, 50%, and 9%, respectively. Patients with organ dysfunction with or without concurrent infection had the lowest survival. Causes of death included: GvHD (10), infection (5), relapse (4), organ failure (3), and poor graft function (1). CONCLUSION: Treatment of PGF with a TCD HSC boost from the original donor is safe and effective with minimal risk of GvHD. Medical status at the time of the boost infusion had a significant impact on outcome. A TCD boost should be considered early in the course of PGF as once complications of persistently low blood counts occur the potential for benefit sharply declines. Disclosures: Small: Pfizer, Inc: Equity Ownership, family member employed by Pfizer, Inc. Perales:Pfizer, Inc: Equity Ownership.

Description: Curative strategies for hematologic malignancies include alloHSCT, which has become a treatment option for older pts, as well as those with more extensive prior therapy and comorbidities. This has stimulated research on the development of less toxic but comparably effective approaches to transplantation at the level of cytoreduction, alternate graft sources, graft manipulation, and GvHD prophylaxis. To this end, between 7/2001 and 12/2005, we administered TCD HSCTs, derived from HLA-M or HLA-MM URDs, to 36 adult pts as treatment for a variety of hematologic malignancies on a clinical trial. The conditioning regimen was designed to reduce regimen related toxicity while preserving adequate immunosuppression to allow for engraftment. The TCD grafts allowed transplantation across HLA disparate pt-donor pairs without the use of additional renal and hepatotoxic GvHD prophylaxis. The conditioning regimen consisted of hyperfractionated total body irradiation (HFTBI) (1375 cGy), thiotepa (5mg/kg) x 2d, fludarabine (25mg/m2) x 5d and antithymocyte globulin (ATG) x 2d. HLA typing was performed by DNA SSOP analyses for A,B,C, DRB1, and DQB1, and donors were matched at ≥8 of 10 alleles. Pts received TCD-PBSC (n=29) or TCD-BM (n=7) from HLA-M (21 pairs) or HLA-MM (15 pairs) URDs. PBSCs were TCD by Isolex 300i CD34+ selection followed by sheep E-rosette depletion, and BMs were depleted with soybean agglutination and sheep E-rosette depletion. The median age was 40.6 (range 18–63)yrs; 10 pts ≥ 50 yrs. Diseases included AML and ALL CR1 (only standard or high risk), AML and ALL CR2, ALL ≥ CR3, acute biphenotypic leukemia, CML in CP, MDS, T-PLL. The median followup is 22 (range 6–55) mos. All evaluable pts engrafted neutrophils, 31 of 35 evaluable pts engrafted platelets. Four pts died of complications prior to platelet engraftment, including one pt with late graft failure. The 100d non-relapse mortality was 20% with most (〉50%) deaths due to infection. The incidence of acute (a) grade II–III and chronic (c) GvHD was low for the entire group of 36 pts at 11% and 28%, respectively, when compared to that of unmodified transplantation. The incidence of aGvHD was 14% and 7%, and cGvHD (majority - limited) was 26% and 30% for HLA-M and HLA-MM transplant pairs, respectively. Estimated 3 yr DFS is 60% for both HLA-M and HLA-MM transplants, and 83% for standard risk and 41% for high risk disease pts. Only one pt has relapsed. These results indicate that a transplantation strategy using HFTBI, thiotepa, fludarabine and ATG followed by TCD PBSC or BM, but without posttransplant immunomodulating agents, is well-tolerated in an older patient group (median age 40 yrs) even with HLA-MM URDs. Although this approach appears to provide an antileukemic effect for acute leukemia pts transplanted in remission of acute leukemia, this will need to be confirmed with longer followup.

Description: Between 05/98 and 06/04, 15 consecutive patients with FA received hematopoietic stem cell transplants (SCT) from alternative donors at our Center. There were 7 males and 8 females aged 5 to 24 years (median 11.5). Hematologic diagnoses included aplastic anemia (AA) (N=5), myelodysplastic syndrome (MDS) in RAEB (N=4), RAEBT (N=1) or acute myelogenous leukemia (AML) (N=5). High risk features included: Age 〉 20 years (n=4), prior multiple transfusions (n=11), prior androgen treatment (n=12), prior infections (n=10), or advanced MDS or AML (n=9). Eight pts had related mismatched donors transplants with respective matching at 3/6 (6/10), 4/6 (6/10), 4/6 (7/10) (n=2)), 5/6 (8/10) (n=3) and 5/6 (9/10) HLA-antigens. Seven pts had unrelated donors transplants with respective matching at 5/6 (7/10), 5/6 (8/10) (n=2), 5/6 (9/10) and 6/6 (10/10) (n=3) HLA-antigens. Cytoreduction included single dose total body irradiation (SDTBI) (450 cGy), fludarabine (Flu) (30 mg/m2 x 5) and cyclophosphamide (Cy) (10 mg/Kg x 4). Immunosuppression included rabbit anti-thymocyte globulin (Thymoglobulin) and tacrolimus for all patients. Grafts were G-CSF mobilized CD34+ and E-rosette negative (E-) peripheral blood stem cell transplants for 12 pts and soybean agglutinin negative (SBA-) and E-rosette negative marrow transplants for 3 pts. Cell doses of the grafts were 1.5 – 29.6 x 106 CD34 cells/Kg and 0 – 26 x 103 CD3 cells/Kg. As evidenced by RFLP or FISH, all 15 evaluable pts were fully engrafted and complete chimeras. Fourteen pts were evaluable for graft-versus-host disease (GvHD). GvHD of the skin and of the gut was suspected in two pts but resolved completely prior to immunosuppressive treatment. With a median follow-up of 2.5 years (range 0.2–6), 13 of 15 pts are alive and 11 of 15 are alive disease-free. There were two deaths: one pt died from sepsis/ARDS at 2 months post SCT and one pt from pneumonitis/ARDS and EBV-infection 6 months post SCT. Three pts relapsed (MDS-RAEB x 1 – AML x 2): One pt relapsed 7 months post transplant, received a 2nd transplant from the same donor following busulfan and Flu and is alive, disease-free 18 months post SCT, while the other two pts are awaiting a second SCT. In summary, this cytoreductive regimen used with T-cell depleted stem cell transplants from unrelated or HLA-mismatched related donors for the treatment of high risk patients with Fanconi anemia, results in rapid hematopoietic engraftment and lymphohematopoietic reconstitution with minimal GVHD and a high disease-free survival.

Description: The standard cytoreduction for bone marrow transplantation (BMT) of pts with HGBpathies has been the combination of Busulfan (BU) and Cyclophosphamide However, for pts with advanced disease, high rates of graft rejection and toxicity were reported. For such high risk pts, a BU and Fludarabine (FLU) cytoreductive combination was used at low dose in the context of non-myeloablative BMT and was associated with a poor outcome with high rates of graft rejection. In view of the low toxicity associated with the BU-FLU combination, we used both agents at higher, potentially myeloablative doses for the cytoreduction of six pts with high risk HGBpathies. Between 12/00 and 04/05, 4 pts with thalassemia (Thal) and 2 pts with sickle cell disease (SCD), including 2 males and 4 females aged 4.6–15.3 years were transplanted using this regimen. All 4 pts with Thal had advanced Lucarelli Class 2 disease, while the 2 pts with SCD had stroke, recurrent vaso-occlusive crises (VOC), sickle lung disease and alloimmunization (n=1) and recurrent VOC, acute chest syndrome and osteomyelitis (n=1). Cytoreduction included intravenous BU (0.8–1 mg/Kg/dose x 14), FLU (30 mg/m2/day x 5) and Rabbit ATG (2.5 mg/Kg x 2). GvHD prophylaxis consisted of Tacrolimus (n=3) or cyclosporine (n=3) and methotrexate (n=5) or Steroids (n=1). Pts received an unmodified BMT from their HLA-identical sibling with total nucleated cell doses of 0.7–5.7 x 108 cells/Kg. The regimen was well tolerated with minimal toxicity. With a median follow-up of 21.5 mo (range 3–55 mo), all 6 pts are disease- and transfusion- free. There was no graft rejection and no GvHD. Chimerism status for pts with Thal was 98–100% donor, 5 mo to 2 years post BMT, while for the 2 pts with SCD, it was mixed with 50 and 80% donor cells at 3 mo and 2 years post BMT. The pt with 50% donor cells received a low graft cell dose (0.7 x 108 nucleated cells/Kg). One additional pt with SCD and a history of 2 strokes and moya-moya disease received BU FLU + melphalan (70 mg/m2 x 2). This pt had minimal post BMT toxicity, and is engrafted with 100% donor cells at 1 year post BMT. In summary, the combination of high dose BU and FLU for pts with high risk HGBpathies was well tolerated and induced full engraftment for pts with Thal, but mixed chimerism for pts with SCD. Nevertheless, all pts so treated survive with normal hematologic function. The addition of melphalan to BU FLU was also well tolerated and could be beneficial in attaining complete myeloablation and full chimerism in pts with SCD.

Description: T cells can be genetically modified to target tumor antigens through the expression of a chimeric antigen receptor (CAR). CAR T cells targeting the CD19 antigen is a novel therapeutic approach for patients with relapsed B cell acute lymphoblastic leukemia (B-ALL). We have previously demonstrated that CAR T cells have a significant clinical benefit in adult patients with relapsed B-ALL. The primary objective of this study (NCT01860937) is to extend the use and test the safety of CD19 specific CAR T cells in a multicenter trial for children and young adults with relapsed CD19+ B-ALL. To date, 24 patients with very high risk (VHR) or relapsed B-ALL have been enrolled on protocol with a median age of 12 years (range 2-20 years) at time of T cell collection. We have treated 9 patients with relapsed B-ALL with a median age 15 years (range 3-22 years) using patient derived T cells expressing a CD19 specific CAR (19-28z). Patients received a dose of 1-3 x 10^6 CAR T cells/kg and complete response (complete remission or complete remission with incomplete count recovery) occurred in 5/9 (55%) patients. Significantly, correlations with response included lower disease burden (as assessed by bone marrow cellularity; p20 fold), Flt-3L (〉55 fold), IL-5 (〉15 fold), IL-6 (〉100 fold), and IL-10 (〉15 fold) were demonstrated in patients with CRS. Monitoring of bone marrow demonstrated peak 19-28z CAR T cell detection within 1-2 weeks following infusion with gradual contracture over 1-2 months. These early results demonstrate the feasibility and significant clinical impact of this approach in patients with relapsed B-ALL. In an effort to more rapidly generate statistically relevant data, demonstrate the "exportability" of this technology between academic institutions, and offer this therapeutic option to a broader number of pediatric patients with chemo-refractory B-ALL we have expanded this trial to include a collaborating institution. The objective of our trial is not to provide an intent-to-treat cohort, but rather demonstrate the tolerability of this technology in patients with relapsed B-ALL. Furthermore, patients meeting disease eligibility were not pre-screened for lymphocyte function prior to collection and/or treatment. Subsequent cohorts of patients will receive 19-28z CAR T cells and will be evaluated for toxicity, persistence of CAR T cells, and for anti-leukemic efficacy. Disclosures Curran: Juno Therapeutics: Consultancy. Off Label Use: CAR T cells for B-ALL. Riviere:Juno Therapeutics: Other: Co-founder, stockholder and consultant. Prockop:Atara Biotherapeutics: Other: I have no financial disclosures, but Atara Biotherapeutics has exercised a licensing agreement with Memorial Sloan Kettering Cancer Center and MSKCC and some investigators at MSKCC have a financial interest in Atara.. Park:Actinium Pharmaceuticals, Inc.: Research Funding; Juno Therapeutics: Consultancy. O'Reilly:Atara Biotherapeutics: Research Funding. Sadelain:Juno Therapeutics: Other: Co-founder, stockholder and consultant. Brentjens:Juno Therapeutics: Other: Co-founder, stockholder and consultant.

Description: Background Acute graft-versus-host disease (aGVHD) is common after double-unit cord blood transplantation (CBT) with an incidence of grade II-IV aGVHD as high as 55% by day 180 in patients transplanted without ATG. aGVHD is associated with increased morbidity and transplant-related mortality (TRM). Mycophenolate mofetil (MMF) combined with a calcineurin-inhibitor is commonly used to prevent GVHD after CBT. However, unlike the 1 gram (gm) every 8 hours dosing that is now standard in adult donor allografts, MMF dosing in CBT has traditionally been every 12 hours. Our center has increased MMF dose from 1 gm every 12 (q12) to 1 gm every 8 (q8) hours in an effort to reduce severe aGVHD after double-unit CBT. However, the efficacy of this intervention is not established and a theoretical concern is that intensified MMF dosing could result in an increased risk of delayed engraftment or graft failure. Methods We evaluated 171 double-unit CBT recipients (median age 39 years, range 0.9-71) transplanted with either myeloablative (MA, n = 133) or non-myeloablative (NMA, n = 38) conditioning for high-risk hematologic malignancies between 10/2005 and 4/2013. CB units were 4-6/6 HLA-A, -B antigen, -DRB1 allele matched to the recipient (16 6/6, 171 5/6, 155 4/6). All patients received GVHD prophylaxis with intravenous calcineurin-inhibitor (predominantly CSA) and MMF from day -3 without ATG. Prior to 9/2009, 80 patients (47%) received MMF 1 gm IV q12 (and those 12 years and ≥50 kg (or 15 mg/kg/dose if 〉12 years but