Search

Background: Inotuzumab ozogamicin (InO) was well tolerated and demonstrated anti-leukemia activity in heavily pre-treated pediatric patients (pts) with CD22-positive relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) in the Phase (Ph) I ITCC-059 study. With the established recommended phase 2 dose (RP2D) (1.8 mg/m2/course, as in adults) a consecutive Ph II study has been performed, sponsored by Erasmus MC and supported by Pfizer (NTR57360). Study design: Pts aged 1-18 years with R/R CD22+ BCP-ALL were included after informed consent was obtained. Key inclusion criteria included, M2/M3 marrow and adequate liver and kidney function. Overall response rate (ORR) was the primary endpoint, and included CR, CRp (ANC >500/µL but PLT ≤50.000/µL) and CRi (ANC ≤500/µL and/or PLT ≤50,000/µL). Secondary endpoints included safety, minimal residual disease (MRD) levels and durability of response. The study consisted of a single-stage design to test the null hypothesis (H0) ORR ≤30% and the alternative hypothesis of ORR >55%. With 25 pts, the study had 80% power to reject H0 at a significance level of 0.05. Central MRD analysis by flow cytometry was considered negative if Results: 32 pts were enrolled (Jun 2019-Apr 2020), including 2 screen failures and 2 pts who did not start treatment due to rapidly progressive disease. The median age of the 28 treated pts was 7.5 years (range 1-17); 19 pts were male (68%); 6 (21.5%) were primary refractory, 16 (57%) had ≥2nd relapse and 6 (21.5%) had 1st relapse post-HSCT (median 2 prior regimens, range 2-7). 50% of the pts had received a previous HSCT, 3 (11%) CAR T-cell therapy and 7 (25%) blinatumomab. Median baseline WBC was 3.1 x109/L (range 0.7-132). At time of data snapshot, 48 courses of InO were administered (range 1-4 per pt); one pt was still receiving InO. Disease response was not assessed in 1 pt (discontinued early due to sinusoidal obstruction syndrome (SOS)), 27 pts were evaluable for efficacy analyses. Twenty-two pts achieved a response (ORR 81.5%; 95% CI 61.9%, 93.7%), all after the first cycle (CR n=14, CRp n=1, CRi n=7). Hence, the primary objective was achieved (P-value When combining these results with pts treated at the RP2D in the Ph I study (n=13), 33/40 (82.5%) achieved a response (94% of whom achieved MRD-negativity). Of 9 primary refractory patients included in Ph I and II, 3 (33%) did not respond to InO. The median follow-up time was 7.3 months (mo). The EFS at 6 and 12 mo was 57.9% (95% CI: 40.3−83.3) and 24.8% (95% CI: 9.8−62.9); and OS at 6 and 12 mo was 61.6% (95% CI: 43.3−87.8) and 54.8% (95% CI: 35.9−83.6), respectively. The median EFS was reached at 6.34 mo (95% CI 2.53, NA). The cumulative incidence of non-response or relapse was 32% and 57% at 6 and 12 mo; 3 pts died in CR (2 due to HSCT complications, 1 due to neurological deterioration considered related to previous CNS leukemia and prolonged intrathecal treatment). Nine of 22 responding pts underwent HSCT (median 35 days after the last InO dose, range 20-72); 4 are still in CR. Three responders received consolidation with CAR T (52, 55 and 215 days after last Ino dose), all are still in CR. Four cases of VOD/SOS were reported. One case occurred during InO treatment (gr 3, resolved). Three of 9 transplanted pts (33%) developed post-HSCT SOS. None of these pts received prophylactic defibrotide. One pt, previously transplanted and treated with CAR T, received 1 course of InO prior to a second HSCT and developed SOS (gr 3), ongoing at the time of death due to multiorgan failure. The other 2 pts developed gr 2 SOS after 2 and 3 courses of InO before their first HSCT, both events resolved. All pts had at least 1 adverse event (AE) during the study and 19 pts reported at least 1 of gr 3-4 AE. The most common AE was fever. Detailed data will be presented at the meeting. Conclusion: InO was well tolerated in this Ph II study which confirmed remarkable activity in these heavily pretreated pts. The ORR was 81.5% with 95% MRD-negativity; 55% of pts remained alive after 1 year. Twelve pts proceeded to consolidation treatment (either HSCT or CAR T). In contrast with the Ph I cohort (where no pts developed SOS post 7 HSCTs), 3 cases of SOS were recorded here after 9 HSCTs. A Ph I cohort of this study combining InO with chemotherapy in R/R pediatric ALL is ongoing. Disclosures Brivio: Pfizer Inc.: Other: Erasmus MC received institutional funding for the study from Pfizer. Rossig:BMS: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Sleight:Pfizer Inc.: Current Employment. Reinhardt:Novartis: Membership on an entity's Board of Directors or advisory committees; CLS Behring: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees. von Stackelberg:Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau. Zwaan:Servier, Sanofi, Daiichi Sankyo, Novartis, Janssen, Roche, Incyte, Pfizer, Celgene: Consultancy; Pfizer, Celgene, BMS: Research Funding; Jazz Pharmaceuticals: Other: Travel funding.

Background Hemophagocytic lymphohistiocytosis (HLH) is an inflammatory condition caused by uncontrolled proliferation of activated lymphocytes and macrophages secreting an excess of inflammatory cytokines. When untreated, primary HLH is invariably fatal. Treatment requires the achievement of remission of HLH prior to allogeneic hematopoietic stem cell transplantation. Despite significant treatment progress, pre-HSCT mortality remains a challenge. In the Etoposide-based HLH-94 and HLH-2004 studies pre-HSCT mortality was 27% and 19%, respectively. A better understanding of the pathophysiology of primary HLH has opened new avenues for targeted immunotherapy. Based on our previous observation concerning the use of Antithymoglobulin in HLH, we propose a new therapeutic strategy with Alemtuzumab in association with steroids and cyclosporine A (CSA) as first line treatment in primary HLH. In contrast to ATG, Alemtuzumab does not activate T lymphocytes while killing them. Therefore, we expect a better tolerance and efficacy of Alemtuzumab. This may have a positive impact not only on survival until HSCT, but also on overall survival and quality of life, especially with regard to long-term neurological sequelae. Methods 24 consecutive treatment naïve patients with genetically confirmed primary HLH had received first line Alemtuzumab in association to steroids and CSA from 01/2009 to 06/2015 in the Unit for Pediatric Immunology in Necker Hospital Paris, as well as two additional patients in 10/2016 and 10/2018 respectively, who could not be included in the prospective trial. From 06/2015 to 06/2019, 29 patients have been enrolled in a multicenter, open, phase I/II, non-comparative, non randomized study (NCT02472054). Patients with lymphohistiocytic activation syndrome who had not received any specific treatment prior to enrollment except steroids and CSA were included. Treatment consisted in intravenous administration of Alemtuzumab in association to Methylprednisolone and CSA. The primary outcome measures is the number of surviving patients until HSCT, secondary outcome measures the number of complete remissions following treatment at Day (D)14, D21, D28. To assess the efficacy of the Alemtuzumab, the time of delay between the first administration of Alemtuzumab and complete remission will be determined. Alemtuzumab Pharmacokinetics will be done. All adverse events are reported. Results Retrospective analysis of 26 patients (pilot study): The median age of patients was 1.9 months (birth - 7 years), 6 patients were neonates. When Alemtuzumab was started, out of 26 patients 12 (46.1%) required intensive care, 8 (30.7%) mechanical ventilation, 13 (50%) had neurological involvement, 9 (34.6%) hepatocellular insufficiency. One 2-month-old Munc13-4 patient died at H+48 after two administrations of Alemtuzumab (total dose 1.5mg/kg) for hepatic failure and acute renal failure. A second patient with Perforin deficiency did not respond neither to three courses of Alemtuzumab (cumulative dose 6.5mg/kg) nor repeated Etoposid, 40mg/kg ATG, or Ruxulotinib. He died at D+65. The 24 remaining patients survived until HSCT (survival 92.3%). As shown in the figure, two patients required additional treatment. Overall 22 patients achieved CR, 2 PR at the time of HSCT. The prospective study enrolled 29 patients from 06/2015 to 06/2019. Median age at onset of HLH was 0.5 years (range 0.02 to 17.2 years), one patient withdrawed consent. 12 patients received one course, 13 two, 2 three and one patient 4 courses of Alemtuzumab. 24 patients with a genetic confirmed HLH predisposition reached the primary endpoint with 22 surviving until HSCT (91,6%). One patient is still awaiting HSCT. The three remaining patients are one CA-EBV patient and a newborn with secondary HLH due to fulminant HSV hepatitis, who both died, as well as a patient with predominant neurological HLH without genetic diagnosis who is in sustained remission without any specific treatment. Detailed results from the completed study will be presented. Conclusions This is the first report on Alemtuzumab as first line approach in the treatment of primary HLH. Our results in more than 50 pediatric patients treated in a pilot study and prospective trial indicate that Alemtuzumab allows controlling HLH activity with a favorable safety and tolerability profile in a very fragile population. 92.3% and 91.6% of patients respectively survived to HSCT. Figure Disclosures No relevant conflicts of interest to declare. Off Label Disclosure: Alemtuzumab (Campath) has been used in a prospective trial to evaluate its efficacy as first line treatment in Familial Lymphohistiocytosis.

INTRODUCTION Diamond-Blackfan Anemia (DBA) is a congenital pure red cell aplasia, secondary to ribosomal protein genetic defects that usually presents within the first year of age and can be associated with congenital abnormalities and increased risk of cancer. Some patients are successfully treated with steroids but most of them remain transfusion-dependent. Stem Cell Transplantation (SCT) represents the only curative option for this disease, however data from literature is scarce and limited to a very small number of cases. In this retrospective study we describe the outcome of SCT in patients with DBA reported in the EBMT data base. PATIENTS AND METHODS The study was conducted on behalf of Severe Aplastic Anemia Working Party of the EBMT and was based on data of patients affected with DBA who underwent SCT and registered in the EBMT Data Base. Clinical information of the disease and details on transplant procedures and follow-up were collected by a specific form distributed to Centres participating in the study. RESULTS Between 1985-2016, 106 patients (60 males-46 females) aged 6.8 yo (range 1-32) underwent SCT from matched sibling donor (58, 57%), unrelated donor (37, 36%) or from other donors (7, 7%) using bone marrow (73, 69%), peripheral blood (21, 20%) or cord blood (12, 11%) as cell source. 91 patients (86%) received a myeloblative regimen which included Busulfan in 66 cases. 86% (80-93%) of patients engrafted by day 28. Median days to neutrophils and platelets engraftment were 18 and 36, respectively. EFS and OS at 36 months were 81% (74-89%) and 84% (77-91%), respectively. OS was significantly higher (p=0.01) in patients CONCLUSION To the best of our knowledge, this is the largest reported cohort of patients transplanted for DBA and having a long follow-up. The very good OS of patients undergoing transplant from both sibling and unrelated donors and the rather low rate of cGvHD confirms that this procedure can be considered an alternative option for transfusion-dependent patients Disclosures Bader: Riemser, Neovii: Research Funding; Medac: Patents & Royalties, Research Funding; Amgen (Brasil), Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy. Risitano:Alexion: Honoraria, Research Funding, Speakers Bureau; Achillion: Research Funding; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Research Funding, Speakers Bureau; Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amyndas: Consultancy; Biocryst: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ra Pharma: Research Funding; Ra Pharma: Research Funding; Alnylam: Research Funding; Alnylam: Research Funding; Achillion: Research Funding. Peffault de Latour:Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding.

Transplantation of 2 unrelated cord blood (UCB) units instead of 1 has a been proposed to increase the cell dose. We report a prospective a randomized study, designed to compare single-vs double-UCB a transplantation in children and young adults with acute leukemia in a remission or myelodysplasia. Eligible patients had at least two 4-6 a HLA-identical UCBs with >3x10(7) nucleated cells/kg for the first and a >1.5x10(7) for the second. The primary end point was the 2-year a cumulative incidence of transplantation strategy failure, a composite a end point including transplant-related mortality (TRM), engraftment a failure, and autologous recovery. Randomized patients who did not a proceed to transplantation due to refractory disease were considered a transplantation failures. A total of 151 patients were randomized and a included in the intent-to-treat analysis; 137 were transplanted. a Double-UCB transplantation did not decrease transplantation strategy a failure (23.4% 6 4.9% vs 14.9% +/- 4.2%). Two-year posttransplant a survival, disease-free survival, and TRM were 68.8% +/- 6.0%, 67.6% a +/- 6.0%, and 5.9% +/- 2.9% after single-unit transplantation a compared with 74.8% +/- 5.5%, 68.1% +/- 6.0%, and 11.6% +/- 3.9% a after double-unit transplantation. The final relapse risk did not a significantly differ, but relapses were delayed after double-unit a transplantation. Overall incidences of graft-versus-host disease (GVHD) a were similar, but chronic GVHD was more frequently extensive after a double-UCB transplantation (31.9% +/- 5.7% vs 14.7% +/- 4.3%, a P=.02). In an exploratory subgroup analysis, we found a significantly a lower relapse risk after double-unit transplantation in patients a receiving total body irradiation without antithymocyte globulin (ATG), a whereas the relapse risk was similar in the group treated with busulfan, a cyclophosphamide, and ATG. Single-UCB transplantation with adequate cell a dose remains the standard of care and leads to low TRM. Double-unit a transplantation should be reserved for patients who lack such units. a This trial was registered at www. clinicaltrials. gov as #NCT01067300.

PV and AL contributed equally Multiple studies from the EBMT registry and others have shown excellent survival rates after allogeneic haematopoietic stem cell transplantation (HSCT)for Wiskott-Aldrich syndrome (WAS) patients (Ozsahin et al, Blood 2008). The importance of myeloid engraftment for full disease correction has also been demonstrated (Moratto et al, Blood 2011). However, the vast majority of HSCTs in these studies were performed with (oral) busulfan/cyclophosphamide-based conditioning and in the early 2000 years or before. In 2005, the inborn errors working party (IEWP) of EBMT and ESID first recommended busulfan/fludarabine (BuFlu) or treosulfan/fludarabine (TreoFlu) based conditioning for primary immunodeficiencies such as WAS, with some centers deciding to add thiotepa (TT) to the conditioning. We performed a retrospective analysis via the EBMT and SCETIDE registries of WAS patients transplanted between 01/01/20006 and 12/31/2016 with these two regimens. The primary objective was to compare the overall (OS) and event-free survival (EFS) after HSCT with either BuFlu±TT or TreoFlu±TT conditioning. Secondary objectives included the influence of either conditioning regimen on acute and chronic GVHD, the degree of donor chimerism, incidence of secondary procedures after HSCT (2nd HSCT, stem cell boost, DLI, gene therapy or splenectomy) and rates of disease-specific complications after HSCT. At the time of this interim analysis, 174 patients were included, 92 (53%) with BuFlu±TT and 82 (47%) with TreoFlu±TT conditioning with a median age of 1.57 years (range 0.21-29.96) at HSCT and a median follow-up of 32.9 months (range 1.5-128.9). The donor was an HLA-matched sibling (MSD) in 30, a matched related donor (MRD) in 5, a matched unrelated donor (MUD, 9/10 or 10/10) in 105, a mismatched unrelated donor (MMUD, 5 years had a worse OS as compared to those 5 years or younger at HSCT (74.9% vs. 90.8%; log-rank test p=0.005). The type of donor had no influence on OS: 96.4% for MSD/MFD, 86.8% for MUD/MMUD and 87.7% for MMFD (log-rank test p=0.4). Whole blood chimerism was complete (>90% donor) in 60/75 evaluable patients (80%) at last follow-up or before secondary procedure (if a patient had one), 39/40 (98%) in the BuFlu±TT group and 21/35 (60%) in the TreoFlu±TT group. Twenty-six patients required a secondary procedure: stem cell boost in 4 patients, donor lymphocyte infusion in 9, 2nd HSCT in 15 and splenectomy in 1. Twenty-two of these 26 (84.6%) are alive and 14 of 16 with available chimerism data have a complete donor chimerism (>90%donor) at last follow-up. The 2-year cumulative incidence (CI) of secondary procedures was higher at 33.9% in the TreoFlu±TT versus 12.8% in the BuFlu±TT group (Gray's test p=0.017), and 2-year EFS (secondary procedure or death as event) was 61.4% in the TreoFlu±TT and 75.0% in the BuFlu±TT group (log-rank test p=0.2). Grade II-IV acute GVHD had the same incidence in both groups (100 day CI 24.4% vs. 26.3%; Gray's test p=0.849) and chronic GVHD of any grade was borderline more frequent in the TreoFlu±TT group (2 year CI 17.2% vs 6.7%; Gray's test p=0.054). The cumulative incidence of disease-specific complications occurring more than 6 months post HSCT (severe infections, bleeding, autoimmunity) was not different between the two groups (6.5% vs. 6.4%; Gray's test p=0.92). There was no malignancy reported after HSCT except for one EBV-post-transplant lymphoproliferative disorder (PTLD) 2.7 months after HSCT. In summary, HSCT with either BuFlu±TT or TreoFlu±TT conditioning reliably cures almost 90% of patients with WAS regardless of donor type. WAS-related complications are very rare events more than 6 months post HSCT. More patients required secondary procedures after treosulfan-based than busulfan-based conditioning. These data confirm the feasibility and efficacy of the regimens currently recommended by the IEWP. Disclosures Slatter: Medac: Other: Travel assistance. Chiesa:Gilead: Consultancy; Bluebird Bio: Consultancy. Kalwak:Sanofi: Other: travel grants; medac: Other: travel grants. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria. Sykora:Aventis-Behring: Research Funding; medac: Research Funding. Zecca:Chimerix: Honoraria. Veys:Pfizer: Honoraria; Servier: Research Funding; Novartis: Honoraria.

Introduction: Inotuzumab ozogamicin (INO) is an anti-CD22-drug conjugate therapeutic agent, in which a cytotoxic agent, calicheamicin, is conjugated to a humanized IgG4 anti-CD22 mAb (de Vries et al., Leukemia, 2012). As CD22 expression is confined to the B-cell lineage and is largely expressed in mature and immature B-cell malignancies, INO represents an attractive drug to treat B-cell acute lymphoid leukemia (ALL). INO has been evaluated in clinical trials and its efficacy has been reported in adult and elderly patients (pts) with ALL (Kantarjian et al., NEJM, 2016; Lancet Oncol 2018 and Cancer 2018). Since half of the total number of cases of ALL occurs in children and teenagers and it is the most frequently diagnosed malignancy in children, with the vast majority arising from B-cell lineage (85%), INO is also a drug of interest for the 15% of pediatric pts who are not cured by current treatments. We here report French pediatric pts with refractory or relapsed (r/r) B-cell ALL who were treated by INO through a compassionate use access program. Methods: French pediatric hematology centers provided retrospective clinical follow-up on pts' ≤ 18 years old affected by r/r B-cell ALL who received at least one dose of INO, provided by Pfizer through a compassionate use program following authorization by the French regulatory agency (ANSM) between 2015 and 2017. All pts were treated according to the adult phase 3 clinical trial dose of 1.8 mg/m2 during the first course divided as followed: 0.8 mg/m2 of body surface at day 1 and 0.5 mg/m2 at day 8 and 15. A second course could be repeated at the same dosage if the response was not complete after the first course. Then the consolidation courses of treatment could be continued at the dose of 1.5 mg/m2 divided as 0.5 mg/m2 of body surface at day 1, 8 and 15, up to 3 total cycles. Results: Eleven pts aged from 3 to 18 years old received INO; and were: 2 between 1 and 10 years old, 4 between 10 and 15 and 5 between 15 and 18. They received from 1 to 3 cycles of INO. They were heavily pretreated, as 6 of them received INO while refractory to the treatment of a first relapse, and 5 of them in treatment of second relapse or more. Prior to INO therapy, 4/11 pts had undergone allogenic hematopoietic stem cell transplantation (HSCT) and 7/11 pts had received anti-CD19 therapy with either Blinatumomab (6/7) or CAR-T cells (1/7). Pre-INO treatment medullary status was M3 (>25% blasts) for 8/11 pts, M2 (5-25%) for 2 pts and M1 ( Eight pts were in complete remission (CR) after one cycle (M2/M3 marrow prior to INO: 7, M1: 1), including 2 pts with an undetectable MRD (< 10-5). These 2 pts received a second cycle of INO and were brought to HSCT; both of them are alive (20 months (m)+, 27 m+). The 6 remaining pts in CR but MRD+ subsequently died: 1) 5 received a second cycle of INO without documentation of MRD negativity. All of them relapsed whatever the following treatment (time to disease progression ranged from 1 week to 17 months). 2) 1 pt was brought to HSCT but died of cardiac failure 3 months after the procedure. As observed in adults, hepatic and hematologic adverse events were observed. All pts developed hematologic toxicities, 10/11 pts with grade 3/4 anemia, neutropenia or thrombocytopenia. Febrile neutropenia of grade 3/4 occurred for 5 pts. Cholestasis with grade 3/4 elevations of GGT or transaminases was noted in 4/11 pts. Sinusoidal obstruction syndrome (SOS) occurred in 1 pt who had previously undergone HSCT, during his first course of INO. Two pts who subsequently underwent HSCT developed SOS during transplant. All of these 3 pts recovered normal hepatic function. None of them died from INO direct toxicities. Conclusion: Toxicities developed by these young patients were very similar to the ones reported in adults with hepatic and infectious toxicities. The incidence of SOS seems significant in patients that underwent HSCT either before or after INO treatment. INO showed promising results in pediatric compassionate use program in our French cohort, similarly to the one reported by Bhojwani D et al. (ASCO abstract, 2017). Its safety and efficacy in r/r B-cell ALL are to be further investigated in pediatric populations within prospective clinical trials currently underway in EU and US. Disclosures Baruchel: Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Amgen: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Travel, accommodations or expenses; Celgene: Consultancy; Servier: Consultancy; Shire: Research Funding.

Background: While therapeutic outcomes in patients (pts) with acquired severe aplastic anemia (SAA) has greatly improved in recent years, results remain poor for pts who are refractory to first-line immunosuppressive therapy (IST) and lack a matched unrelated donor. We conducted a prospective multi-center phase II uncontrolled trial to assess the efficacy and safety of cord blood transplantation (CBT) in refractory SAA pts (NCT 01343953). Patients and methods: Pts with SAA refractory to IST with anti-thymocyte globuline (ATG) and ciclosporin (CsA) were eligible in case of no existing matched unrelated donor but available one or two unrelated CB units containing alone or both together more than 4 x 107/Kg frozen nucleated cells/Kg (no more than 2 out of 6 HLA mismatches allowed between each CB unit and the pts). Pts with isolated bone marrow cytogenetic abnormality (absence of morphologic evidence of myelodysplastic syndrome) were also eligible. The conditioning regimen consisted of fludarabine 30mg/m2 (D-6 to D-3), cyclophosphamide 30mg/kg (D-6 to D-3), ATG (thymoglobulin) 2.5mg/kg at D-3 and D-2 (5mg/Kg total dose) and total body irradiation (2 Gray) on D-2. All pts received one injection of anti-CD20 (150 mg/m2) to prevent EBV reactivation (D+5). CsA was given alone as prophylaxis for graft versus host disease (GVHD). The trial used the Fleming's Single Stage Phase II Design, with sample size computed to demonstrate an improved overall survival (OS) rate at one year from 20% up to 50%, with type I and type II error rates set at 0.05. A minimum sample of 25 pts was required, with a minimum number of 9 pts alive at one year needed to indicate treatment efficacy. Secondary endpoints included cumulative incidences (CumI) of engraftment, acute and chronic GVHD (aGVHD and cGVHD), infections, relapse and late cause of death. Results: 29 pts were included between June 2011 and October 2015. One pt was diagnosed with dyskeratosis congenita and a matched unrelated donor was identified for another pt between inclusion and anticipated date of CBT (exclusion criteria). One pt died before CBT due to a septic shock (D+4 after inclusion). Analyses were conducted in the remaining 26 pts. Median time between SAA diagnosis and CBT was 12 months (interquartile range (IQR) 8.7 to 17.8). All pts received at least one course of IST before CBT (2 courses, n=8). Twenty-three pts received 20 or more transfusions before CBT. BM karyotyping showed 2 pts respectively with monosomy 7 in 4 and 15 mitoses as well as one pt with trisomy 8 in 4 mitoses before CBT. Eight pts (31%) have a PNH clone (median 4.5% [IQR: 3.1-9.7]). Median age at time of CBT was 16 years (IQR 8.25 to 23) and median follow-up is 13.2 months (IQR 4.1 - 23.5). Three out of 26 pts incorrectly received twice the dose of ATG (10mg/Kg total dose) due to protocol violation. Sixteen pts received one CB and 10 received two CB units. Median number of nucleated cells infused was 3.7 x 107/Kg (IQR, 3-4.9) and CD34+ cells infused was 1.4 x 105/Kg (IQR, 1.0-1.9). Myeloid engraftment occurred in 23 pts, with a 60 day-CumI of neutrophil engraftment of 88.5% with full chimerism for all of them. Three pts did not engraft (2 deaths at D71 and D92 and one successful second HSCT). The 100 day-CumI of grade II-IV acute GVHD was 40% (95% CI, 20-60) (8 grade II; 0 grade III; 2 grade IV). Among the 23 pts alive at day 100, five developed cGVHD leading to a one-year CumI of cGVHD at 27% (95% CI, 7-47) (severe cGvHD in 2 pts). During follow-up, 8 pts experienced a total of 18 grade III infections with a 6-month CumI of 32% (95% CI, 13-51). None of the pts presented post-transplant EBV-related lymphoproliferative disorder. Immune reconstitution is shown in Figure 1. Three pts died before 1 year due to non-engraftment (n=2) and infection (n=1, one of those who received twice the dose of ATG). With 23 pts alive at 1 year, the primary objective of the study was thus reached. The one-year treatment related mortality (TRM) was 15% (95%CI, 4-35). One additional pt who had also received twice the dose of ATG died (severe cGvHD) after one year (at 13.6 months), resulting in a 14-month OS of 81% (95%CI, 66-100) (Figure 2). Conclusion: CBT with at least 4 x 107/Kg frozen nucleated cells/Kg after a FLU-CY-TBI-ATG conditioning regimen gave rise to very encouraging results in this particular high risk SAA refractory population. Pediatric and young adult SAA pts who are refractory to first-line IST should now be considered either way for matched unrelated donor or CBT. Disclosures Peffault de Latour: Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

To the editor: We have read with great interest the comprehensive and detailed review on hematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD) published by Hsieh et al in a recent issue of the journal.[1][1] As emphasized by the authors, allogeneic HSCT is currently the only

Abstract 1964 Rationale: HSCT is the only curative treatment for Fanconi Anemia (FA) pts with either bone marrow failure or MDS/Leukemia. Due to characteristic chromosomal instability, the poor outcome of FA pts transplanted after so-called conventional myelo-ablative conditioning regimen has been proved. Then, reduced-intensity conditionning regimen (RIC) has been considered for years as a model for allogeneic HSCT in FA pts. The use of fludarabine-based cond' regimen from about 2000 increased dramatically the overall survival of FA pts. Different Flu-based RIC were developed. Patients and method: Between Feb'02 and Dec'10, 17 FA pts from 3 academic French centers were included: 11 from R. Debre hospital, 5 from St Louis hospital and 1 from J. de Flandre hospital. All pts underwent HSCT because of bone marrow failure. They presented no MDS or leukemia. All time-to-event outcomes were counted from the date of HSCT to the date of event or date of last follow-up, except acute GVHD that was arbitrarily censored at 200 days. Death was considered as a competing risk in analyses of neutrophil and platelet recovery and chronic and acute GVHD. Overall survival was estimated using Kaplan-Meier product-limit estimator. For competing risks analyses, cumulative incidences were estimated using usual methodology. Results: Median age at diagnosis and at HSCT were 4.7 years (range 1,8-9,3) and 7,4 years (range 4,4-15,2), respectively. 12 pts presented with less than 3 FA-related malformations and 5 with more than 3 malformations. 2 patients received more than 20 transfusions before HSCT, whereas 8 pts received less than 20 transfusions and 7 patients did not received any. 2 patients received androgen therapy before HSCT. All patients received the same RIC i.e. fludarabine 30mg/m2/d × 3d, cyclophosphamide 10mg/kg/d × 4d and IV busulfan (Bu) 0.75 of body weight- adjusted recommended dose (equivalent to 6.4mg/kg total dose of oral Bu). This RIC did not contain any irradiation. Graft versus-host disease (GvHD) prophylaxis consisted of CSA associated with MMF or corticosteroids. Donors were either matched related (sibling, n= 6; other, n=2) or unrelated (10/10, n= 6; 9/10, n= 3). Stem cell sources were BM (n=10), UCB (n=4) and PBSC (n=2). 9 out of 17 pts had a donor from the same gender whereas 4 male recipients received transplant from female donor. CMV status were −/−, −/+, +/− and +/+ for 8, 4, 1 and 4 D/R pairs, respectively. Median follow-up was 32 months (range 3–102). Successful engraftment was obtained in all patients with a median time for neutrophil recovery of 17 days (range 10–42). All patients presented with 100% donor chimerism. One patient experimented secondary graft failure and died at D291 from infection and renal failure. During transplant procedure, 13 pts experimented at least one severe infectious complication (staphylococcus n=2; pseudomonas n=1; aspergillus n= 2; candida n=2; viral reactivation n= 13). 1 pt presented with moderate hepatic veno-occlusive disease. Five pts died from TRM and 12 pts remained alive in a good health condition. 36 month OS was 69% (95%CI 50 to 96). Cumulative incidence of grade 2 to 4 acute GVHD was 71% (95%CI: 41–87). 5 pts presented with either limited (n=4) or extensive (n=1) chronic GvHD and 36 month cumulative incidence of chronic GVHD was 33% (95%CI 11 to 58). To date, no pt had secondary malignancy. Discussion: Our study confirms the good results obtained by other groups when using flu-based RIC in FA pts. Indeed, satisfying engraftment and long-time survival rates were obtained without any TBI, irrespective of the stem cell source and the donor type. However, we have a concern regarding the cGVHD rate we obtained. As demonstrated by an on-going study of EBMT registry, the risk of secondary malignancy in these pts is statistically correlated to cGvHD. Then, this rate still remains probably too high in our study, even though only one pt presented with extensive cGvHD and no pts developed any secondary malignancy. But this could be explained by the short follow-up. Suppression of one alkalyting agent may reduce both cGVHD incidence and other tissue injuries leading to secondary malignancies. Then, we claim for suppression of Bu for related donor HSCT. In FA pts receiving transplant from unrelated donor, the relative impact of either low-dose IV-Bu – as we used here - or low-dose irradiation on toxicity and especially development of secondary malignancies remains to be evaluated. Disclosures: No relevant conflicts of interest to declare.

Abstract 534 Introduction: There is increasing information about reduced intensity conditioning regimen AlloHSCT (Allogeneic Hematopoietic Stem Cell Transplantation) in children. The safety of this approach is now well established but data regarding efficacy are limited and the role in pediatric cancer has yet to be defined. Materiels and methods: We report results of a French pediatric AlloHSCT protocol with ATG-fludarabine (180 mg/m2) - Busilvex (3.2 at 4.8 mg/kg/d for 2 days) conditioning regimen. Related, unrelated bone marrow (BM) and Peripheral blood stem cell (PBSC) donors and Cord blood units (CB) were allowed. In case of CB a TBI 2 grays, Cyclophosphamide 50 mg/kg, Fludarabine 100 mg/m2 conditioning regimen was recommended. GVH prophylaxis consists in cyclosporine alone. A rapid discontinuation of systemic immunosuppression and re-injecting donor lymphocytes to initiate graft-versus-tumor effect are based on tumor assessment and blood chimerism. Inclusion criteria are children with malignancies that can be potentially cure by allograft but a conventional conditioning regimen being impossible due to toxicity and children with solid tumor or hematological malignancy remaining unresponsive to the reference strategies according to French best practices in pediatrics. Results: From April 2007 to April 2010, 40 RIC AlloHSCT were performed in 10 different French pediatric graft centers: 13 Hodgkin Lymphoma, 7 acute myeloblastic leukaemia, 2 acute lymphoblastic leukaemia, 6 neuroblastoma, 8 rhabdomyosarcoma, 3 desmoplastic tumor and 1 Ewing sarcoma. Median age at transplantation was 15 years and median time from diagnosis to transplant was 18 months. Before transplant, 15 patients are in complete response and 25 patients (14/18 solid tumors) have active disease (11 progressive, 14 partial response). 21 had already received a myeloablative therapy (18 autograft and 3 allograft). Graft source was PBSC in 17 cases (7 related and 10 unrelated), BM in 18 (10 related and 8 unrelated), and 5 CB. The RIC Bu-flu conditioning regimen permits rapid engraftment without major toxicity contrary to the Cy-TBI in CB. 1 patient had primary graft failure: 1 CB and 5 patients experienced secondary graft failure: 3 CB, 1 PBSC and 1 BM. Median time to reach an ANC of 0.5 109/l was 16 days. Median time to reach a platelet count of 20 × 109/l was 2 days. Platelet count did not decrease below 20 109/l in 10 allografts. At day 30 post-transplant, chimerism is mainly donor for 30 and partial for 6 children. At day 100 post transplant, 4 out of 6 with initial mixed chimerism were converted into full donor chimerism. 8 patients received DLI and 17 patients experienced acute graft versus host disease (GvH) (2 grade IV and 15 grade ≤ II). A low day 365 TRM of 5% is reported in these heavily pre-treated patients. With a median follow-up of 15 months, the estimated 2 yr overall survival (OS) was respectively 57 % (71% for hematological malignancies and 42% solid tumors) (fig 1) and event free survival (EFS) 36% (50% for hematological malignancies and 19% solid tumors). Univariate analysis of EFS and OS showed no effect of related versus unrelated stem cell sources and BM versus PBSC. Our analysis identified a group of patients, who had no measurable disease at transplant, with a 2 yr OS and EFS of 86%. In term of efficacy, we observe a graft versus lymphoma effect in patients with advanced active Hodgkin lymphoma. Concerning solid tumors, all children included had a very bad prognosis and detectable disease before transplant. Our results may suggest that an immune-mediated effect cannot be excluded in some refractory solid pediatric tumors particularly in neuroblastoma. The main cause of failure of this approach is disease progression. Immunologic approaches after transplantation may help cure more of these very-high-risk patients. Conclusion: Even if further follow up is needed, this prospective study suggest that RIC regimen provides promising outcome in children previously not eligible for myeloablative AlloHSCT. This study “RICE” was registered at www.clinicaltrials.gov as NCT 007 50 126 Disclosures: No relevant conflicts of interest to declare.

Outcomes in the treatment of sclerodermatous chronic graft-versus-host disease (cGVHD) are generally disappointing. Imatinib mesylate enables selective, dual inhibition of the transforming growth factor beta (TGFβ) and platelet-derived growth factor (PDGF) pathways. Recently, the drug’s effects on fibroblasts have been reported in both in vitro and in vivo studies. Inhibiting fibroblast growth (and thus decreasing collagen production in dermal fibroblasts) is thus a logical therapeutic approach. Here, we report on our experience with 12 patients who received imatinib mesylate for refractory sclerodermatous cGVHD following allogeneic stem cell transplantation (allo-SCT). The patients’ characteristics were as follows: median age, 35 years (range: 15–59); 7 male recipients, 6 female donors; 4 cases of CML, 4 MDS, 2 ALL and 2 Hodgkin’s lymphoma. The patients had received either myelo-ablative conditioning with standard GVHD prophylaxis based on cyclosporine and short-course MTX (n=9) or nonmyelo-ablative conditioning with cyclosporine and MMF. Seven patients received a marrow graft and 5 received a peripheral blood graft. All displayed refractory, chronic, sclerodermatous GHVD with at least 3 lines (range 3–6) of prior immunosuppressive therapy. The modified Rodnan skin score was used to assess the extent of skin damage. Glivec was initiated at a dose of 400 mg/day between 16 and 119 months post-transplantation (median: 44). Despite an imatinib dose reduction and the administration of various symptomatic treatments, 4 patients (33%) had to discontinue their treatment soon after its initiation (range: 16–64 days) because of intolerance (especially muscle cramps) and were not evaluable in terms of the efficacy criterion. Other side effects reported were parenthesis, diarrhea and edema. In the remaining patients, the scleroderma symptoms improved within three months of treatment initiation. At the time of this report, all patients were alive and those who tolerated imatinib mesylate have experienced a complete or near-complete response (n=4) or partial response (n=4). All responders (except for one who discontinued the drug 157 days after initiation, due to cramps) were still on the treatment, after a median time period of 216 days (range: 80–2053). This retrospective report shows that when imatinib mesylate is well tolerated, it is effective in patients with refractory sclerodermatous cGVHD and is thus a promising candidate for the treatment of this complication. This study should provide useful background information for building prospective, multicenter studies.

One of major hurdles to achieving good patient outcomes and survival rates in allogeneic stem cell transplantation (allo-SCT) after myeloablative conditioning is the high rate of transplant-related mortality (TRM). Much progress in supportive patient care has been accomplished over the last decade-notably the use of allelic HLA-matching (Yakoub-Agha, JCO 2006), the introduction of enteral nutrition (Seguy, Transplantation 2004), the development of wireless video-capsule endoscopy for the management of post-transplant diarrhea (Yakoub-Agha, Transplantation 2005), the availability of broad-spectrum antifungal prophylaxis, the use of busulfan IV instead of PO in the conditioning regimen, limitation of the use of ATG in graft-versus-host disease (GVHD) treatment and dose reduction when the latter drug is used in conditioning. Although all these various modifications have had a positive impact on short-term patient outcomes, their impact on long-term survival is still unclear. Hence, the main objective of the present study was to evaluate allo-CST outcomes as a function of the transplantation period. A total 445 patients have undergone post-myeloablation allo-CST in our department. The patient distribution over the time was as follows: prior to 1998 (first period): n=133; between 1998 and 2003 (second period): n=154; between 2003 and 2007 (third period): n=158. Only the first transplant for a given individual was taken into account. Kaplan-Meyer curves were plotted for 100-day survival, 180-day survival and 3-year survival for each time period. Setting aside the clear differences in supportive care methods, the three groups were well matched in terms of disease diagnosis, disease status at transplant and the main recipient and donor characteristics. It is noteworthy, however, that the median age of patients increased over time. Mean 100-day survival was 86 days (95% CI: 81–90), 93 days (95% CI: 90–96) and 96 days (95% CI: 94–98) for the first, second and third periods, respectively (p

Nonmyeloablative (NM) regimens extended the application of allogeneic transplantation (AT) to older and/or medically unfit patients ineligible for high-dose conditionings. Moreover, several patients are offered AT after failure of prior lines of therapy. We retrospectively evaluated 108 patients, median age 51 (16–67), with advanced or heavily pre-treated hematological cancers [19 acute myeloblastic (AML) and 1 lymphoblastic leukemia (ALL); 8 myelodysplastic syndrome (MDS); 9 chronic myeloid (CML) and 9 chronic lymphocitic leukemia; 3 myelofibrosis (MF); 48 myeloma beyond first line treatment; 8 Hodgkin’s and 8 non-Hodgkin’s lymphoma) who underwent NM-AT at 12 Italian transplant Centres. Median time between diagnosis and transplant was 20 months. Sixty-one% of patients had failed at least one prior line of therapy, including 36 refractory or relapsed patients after 1 or more autologous transplants. At allografting, 15 patients had disease at lower risk of relapse (AML and ALL in first complete remission (CR), MDS without blast excess, CML in first chronic phase, untreated MF). Forty-two patients had active disease. The comorbidity score was evaluated with an AT-specific comorbidity index (CI) as described by Sorror et al: 51 patients had CI=0, 42 CI=1–2 and 15 CI≥3. Patients were conditioned with fludarabine 90 mg/m2 and 2 Gy total body irradiation. GVHD prophylaxis consisted of cyclosporine and mycophenolate mophetile. Graft failure was observed in 1 patient and rejection after disease recurrence in 4. After a median follow-up of 28 months post-allografting, 58 (54%) had refractory/progressive disease and 36 (33%) were in CR, including 23 who were not in CR at transplant (p

The use of Gemtuzumab-Ozogamicin (GO), an anti-CD33 monoclonal antibody, is associated to a 20–30% response rate in refractory/relapsed AML. We have reviewed the efficacy and the tolerance of a combination of GO plus cytarabine (GOCYT) given to children with refractory/relapsed AML in order to improve the response rate. This retrospective analysis includes 17 children (9M, 8F) who received the same induction schedule on a compassionate-use basis between may 2004 and june 2006: GO 3 mg/m2/d D1, D4, D7 plus cytarabine 100 mg/m2/d CIV for 7 days. In addition, 6 patients received a consolidation course with GO 3 mg/m2 D1 plus cytarabine 100 mg/m2/d D1 to D7 and 1 patient received GO 3 mg/m2 monthly for 4 doses. Median age at diagnosis of AML is 4.5 y (0.4–16.7). The patient distribution is: de novo AML: 13; biclonal (T and myeloid) acute leukemia: 1; erythremia: 1; t-AML: 2. Initial caryotype was unfavourable in 6 cases, intermediate in 9 and favourable in 2. Patient’s status at GOCYT start were as follows: 2 pts refractory to 1st line therapy (t-AML: 1, M7: 1); 8 pts in refractory first relapse (median time to relapse: 7.25 m, 5–19); 6 pts in relapse after BMT (median time to relapse: 13.5 m, 10.5–111); 1 untreated pt (del(5q) t-AML). CD33 expression was positive in all cases. The median time between initial diagnosis and GOCYT administration is 11.5 m (3–116). MFU is 5 months (1–21). Ten responses were obtained after GOCYT induction (59%): CR: 2, CRp: 4 and PR: 4. Noteworthy, 3 of 7 responders who received a consolidation course with GO improved their response (PR to CR: 2, PR to CRp: 1). Lastly, a subsequent BMT could be performed in 7 responders. Six pts were in leukemic failure and 1 pt died from invasive aspergillosis without bone marrow evaluation. Grade 3 and 4 side effects were: hematologic (17, 100%); documented infections (5): invasive aspergillosis (2 including one responder), pulmonary reactivation of aspergillosis (1), streptococcus oralis septicemia (1), candida kefyr septicemia (1); fever and neutropenia without documented infection (6); hyperbilirubinemia (1); hypertransaminasemia (1); sinusoidal obstruction syndrome SOS (0). Among the 7 patients alive at point date, 6 were responders to GOCYT. Conclusion: a high response rate (59%) was objectived in children with heavily pre-treated refractory/relapsed AML allowing a subsequent BMT in 7. A consolidation course improved the quality of the response in some cases. Despite the limitations of this study, the response rate seems higher than the one observed in phase I–II or compassionate-use pediatric studies using GO alone. No unexpected toxicity was seen. Remarkably, no SOS was observed despite previous BMT in 8 out of the 17 children and a second BMT was feasible in responding pts. GOCYT should be tested prospectively in a largest pediatric AML population.

Survival after HSCT from HLA-identical siblings is inferior in SAA patients 30 years or older as compared with younger patients, with long-term overall survival of 58% and 80%, respectively (Bacigalupo et al, Semin in Hematol 2000). In order to improve survival in patients >30 years, the use of a less toxic regimen including low dose cyclophosphamide (500 cells/μL) and platelet (PLT >50 000/μL) recovery occurring at a median of 18 days (range 12–28 days), and 26 days (range 11–272 days) after transplant, respectively. Acute GVHD occurred in 3 patients with a maximum grade II in 2 patients and grade III in one. Among 11 evaluable patients, six developed chronic GVHD (limited in 3 cases). Four patients died of infection (n=3) or multi-organ failure (n=1), within the 3 months post-HSCT for 3 of them. With a median follow-up of 28 months (range 11–48 months), 10/14 patients survived with long-term engraftment and full (n=8) or mixed (n=2) donor chimerism (KM probability of long-term survival 71%-see figure). In conclusion, reduced intensity fludarabine-based conditioning regimen is feasible in SAA patients over the age of 30 and produces encouraging survival: a prospective trial is being conducted within the European Group for Blood and Marrow Transplantation (EBMT). Figure Figure