ALBERT

Description: The use of in vivo Alemtuzumab in reduced intensity conditioning (RIC) stem cell transplantation for AML has been reported to be associated with low non-relapse mortality (NRM) and favourable survival outcomes. However, Alemtuzumab depletes the alloreactive donor T cells and recipient antigen presenting cells that mediate graft versus leukaemia (GvL) and graft versus host disease (GvHD). We report the analysis of 90 patients from the British Society for Blood and Marrow Transplantation (BSBMT) registry comparing T-cell replete and Alemtuzumab-containing protocols in HLA-identical sibling RIC transplants for AML. Patient characteristics were: median age at diagnosis-50 years; 46%-male, 54%-female; diagnostic karyotypes according to MRC AML criteria-13% good risk, 76% standard risk, 11% poor risk; 67%-CR1, 24%-CR2, 9-refractory/relapsed disease/PR. Conditioning protocols were: fludarabine/melphalan (66%), fludarabine/busulphan (17%), fludarabine/cyclophosphamide (11%), others (6%). 51 patients (57%) received in vivo Alemtuzumab and 37 patients (41%) did not receive any T-depleting antibodies. 2 patients (2%) received ALG/ATG and were excluded from subsequent analyses comparing the effect of Alemtuzumab with T-replete transplants. The median CD34 cell dose was 4.41x106/kg (0.77–15.8). The actuarial overall survival (OS) and progression-free survival (PFS) at 5 years for all patients were 53% and 47% respectively. The NRM and relapse risk (RR) at 5 years were 16% and 49% respectively. The majority of the relapses were within 2 years of transplant. Acute GvHD was either absent or Grade I in 75 patients (84%). Grade II-IV acute GvHD developed in 15 patients (16%). Extensive chronic GvHD occurred in 18/65 surviving ≥100 days (28%). A complete hematological remission(CR) at transplant predicted for OS at 3 years with 54% survival for CR1, 57% survival for CR≥2 and 0% survival for PR/relapse/refractory disease (p

Description: Abstract 1181 Poster Board I-203 MNGIE is an autosomal recessive disorder of nucleotide metabolism due to TYMP gene mutations that cause loss of activity of thymidine phosphorylase (TP). As a result, thymidine (Thd) and deoxyuridine (dUrd) plasma and tissue levels increase and cause nucleotide pool imbalances. This leads to instability of mitochondrial DNA with loss of mitochondrial respiratory chain functions. Clinical consequences manifest as a multisystemic disease with severe gastrointestinal dysmotility, most severe cachexia (BMI 10-17 kg/m2 in our patients), ptosis and/or ophthalmoparesis, peripheral neuropathy and leukencephalopathy. While TP is not expressed in all tissues, cellular and plasma Thd and dUrd levels appear to be in equilibrium among all body compartments. Mononuclear white blood cells and platelets are rich in TP activity and can transiently restore TP activity upon transfusions. Therefore allogeneic HSCT was tested as a permanent replacement therapy by several teams. A coorperative group under the auspices of the WBMT collected the global experiences. So far, 10 patients underwent an attempt for HSCT between 2005-2009. One patient stopped conditioning due to toxicity and did not proceed to transplantation. Nine patients had 12 allogeneic HSCT. They were 6 males and 3 females with a median age of 28y (range 10-41y) at transplantation. All were symptomatic at time of HSCT (5 on parenteral nutrition). A variety of different conditioning regimens and GvHD prevention strategies were used. Fludarabine was included in all conditioning regimens, combined with busulfan or cyclosphoshamide, melphalan, thiotepa or TBI. T cell depletion (TCD) with ATG, alemtuzumab or in vitro TCD was performed in 10 HSCT. GvHD prevention with sirolimus or calcineurin inhibitors was used in combination with mycophenolate mofetil or methotrexate. Graft source for first transplants was peripheral blood stem cells (PBSC) in 4, bone marrow (BM) in 3 and cord blood in 2. PBSC and BM donors were HLA-identical siblings in 2, phenotypic identical parent in 1 and unrelated donors in 4 (3 with 10/10 HLA-match, 1 with 9/10-match). Engraftment was problematic. Three primary graft failures and two late graft failures were observed. A second HSCT was performed in three patients, all engrafted but two died due to TRM. The two patients without a second HSCT died from their disease. Four patients developed acute GvHD grade I-IV. To date, five patients are alive 8-48 months posttransplant, three after related PBSC-HSCT, one after unrelated BM-HSCT (10/10-HLA identical), one after two HSCTs with BM and PBSC respectively from the same unrelated 10/10-HLA identical donor. In all of these patients metabolism normalized as measured by normal Thd and dUrd levels. All surviving patients are off parenteral nutrition without further weight loss or increase in body weight. Gastrointestinal symptoms improved and in the two patients with the longest follow up a slight improvement of neurological symptoms can be observed now. Further time is needed to determine whether other disturbed organ functions will be reversible. Conclusion: Allogeneic HSCT can restore full metabolic function and halt and restore clinical signs and symptoms in this otherwise unrelenting progressive disease. Engraftment was identified as a key obstacle. Still, the optimal transplant regimen needs to be defined to improve patients' outcome. A common consensus transplant protocol and disease specific pre- and posttransplant evaluation protocol was developed with participation of all involved teams. Disclosures: Gratwohl: Amgen: Research Funding; Roche: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding. Hirano:Athena Diagnostics: Speakers Bureau; Pfizer: Research Funding.

Description: BCR-ABL negative myeloproliferative neoplasms (MPNs), such as polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) are chronic myeloid malignancies characterized by overproduction of hematopoietic cells. JAK2 mutations are found in most patients with PV, and in only 50-60% of patients with ET and MF. JAK2 mutation testing has greatly simplified MPN diagnosis, but distinguishing JAK2-wildtype ET from reactive thrombocytosis remains a diagnostic challenge. Mutations in signalling pathways (MPL, LNK) and epigenetic regulators (TET2, DNMT3A, IDH1/2, EXH2, ASXL1) have been found in a minority of MPNs. However genome-wide data are lacking and the pathogenesis of MPNs that do not harbor JAK2 or MPLmutations remains obscure. Methods Exome sequencing was performed in 151 MPN patients on matched tumor and constitutional samples. CALR status was assessed in 3412 samples using Sanger sequencing and analysis of exome/genome sequencing data. Presence of CALR mutations in hematopoietic stem and progenitor cells was assessed by flow sorting and sequencing. Phylogenetic trees were established using hematopoietic colonies. Calreticulin cellular localisation was assessed in patient samples and cell lines expressing CALR variants by flow cytometry and immunofluorescence. Results Exome sequencing identified 1498 somatic mutations with a median of 6.5 mutations in PV and ET, and 13 in MF (MF vs ET, P=0.0002; MF vs PV, P=0.008). JAK2V617F was found in all cases of PV (n=48), 56% of ET (35/62), and 69% of MF (27/39), and MPL mutations in 7 ET and MF cases.  Mutations in epigenetic regulators TET2, DNMT3A, ASXL1, EZH2, and IDH1/2 were identified in 22, 12, 12, 4, 3 patients respectively, and components of the splicing machinery (U2AF1, SF3B1 or SRSF2) were mutated in 9 patients.  Mutations in rare genes reported to be mutated in MPNs were found in four patients (1 CBL; 2 NFE2; 1 SH2B3/LNK). We found novel somatic mutations in CHEK2 (1 PV, 1 ET and 1 MF) which have not been previously reported in MPNs.  The mutation spectrum showed a predominance of C〉T transitions. Pairwise associations between MPN genes demonstrated that ASXL1 and SRSF2 mutations were positively correlated with mutations in epigenetic modifiers. Novel somatic mutations in calreticulin (CALR) were identified by exome sequencing in the majority (26/31) of JAK2 or MPL unmutated patients. CALR and JAK2/MPL mutations were mutually exclusive, and 97% of patients harbored a mutation in 1 of these 3 genes. In an extended follow up screen of 1345 hematological malignancies, 1517 other cancers and 550 controls we found CALR mutations in 71% of ET (80/112), 56% of idiopathic MF (18/32), 86% of post ET-MF (12/14) and 8% of myelodysplasia (10/115), but not in other myeloid, lymphoid or solid cancers. Compared to JAK2-mutated MPNs, those with CALR mutations presented with higher platelet counts (Wilcoxon rank-sum, P=0.0003), lower hemoglobin levels (Student’s t test, P=0.02) and showed a higher incidence of transformation to MF (Fishers exact, P=0.03). All CALR mutations were insertions or deletions affecting exon 9, with 2 common variants L367fs*46 (52 bp deletion) and K385fs*47 (5 bp insertion). Loss of heterozygosity over CALR was seen in a minority of patients. Of 148 CALR mutations identified, there were 19 distinct variants. Remarkably, all generated a +1 basepair frameshift, which results in loss of most of the C-terminal acidic domain of the protein as well as the KDEL Golgi-to-endoplasmic reticulum (ER) retrieval signal, raising the possibility of compromised ER retention. Mutant proteins were readily detected in transfected cell lines and localised to the ER in the same manner as wildtype CALR, without Golgi or cell surface accumulation. These results are consistent with studies reporting KDEL-independent mechanisms of ER retention. Mutation of CALR was detected in highly purified hematopoietic stem/progenitor cells. Clonal analyses demonstrated CALR mutations in the earliest phylogenetic node in 5/5 patients, consistent with it being an initiating mutation in these individuals. Conclusions We describe the mutational landscape of BCR-ABL negative MPNs and demonstrate that somatic mutations in the endoplasmic reticulum chaperone CALR are found in the majority of patients with JAK2-unmutated MPNs. These results reveal a novel biological pathway as a target for tumorigenic mutations and will simplify diagnosis of MPN patients. Disclosures: Bowen: Celgene: Honoraria. Harrison:S Bio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Shire: Speakers Bureau; Celgene: Honoraria; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Vannucchi:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Description: Background: Toxicities following allogeneic hematopoietic stem cell transplantation are specific to the conditioning regimen used and its intensity. Therefore, we hypothesized that the hazard of individual comorbidities is dependent on the conditioning agents and their dose. The aim of this analysis was to study, in a regimen specific manner, the impact of individual comorbidities (cardiac disease, severe pulmonary disease, and diabetes mellitus) on mortality. Methods: We included a multi-center cohort of 3,338 patients from the registry of the Acute Leukemia Working Party of the European Society of Blood and Marrow Transplantation (EBMT), who underwent first allogeneic HSCT for treatment of AML in all disease stages, transplanted between 2005 and 2016. Patients included received grafts from a matched sibling or 10/10 HLA-allele matched unrelated donor, and who were conditioned using one of 7 common regimens (Busulfan [BU[/Cyclophposphamide [Cy], Cy/Total Body Irradiation [TBI], Flu [Fludarabine]/Bu at reduced-intensity [RIC] dosage, Flu/Bu at myeloablative [MAC] dosage, Flu/Melphalan [Mel], Flu/Treosulfan [Treo], Flu/TBI). Regimens were excluded from a given analysis if fewer than ten overall mortality events occurred among patients with or without the studied condition. We constructed a multivariable Cox model for the outcome of overall survival, adjusted for key transplantation variables, including patient age, disease status, and donor type among others. For each comorbidity, separate models were constructed within each of the seven regimens, and the comorbidity's hazard ratio was extracted. Using the same method, the hazard ratio across all regimens, as well as in the myeloablative and the reduced-intensity setting, was obtained. Results: The median age was 55 years; 70% of patients were in first complete remission (CR), and 54% of patients received grafts from matched sibling donors. The most common regimens studied were Flu/Bu at a reduced-intensity dose (22%), Flu/Mel (20%) and Bu/Cy (16%, Table 1). We find that the studied comorbidities were associated with different degrees of added risk for overall mortality in each regimen studied. For cardiac disease, hazard ratios (HR) ranged from 1.00 (95% CI: 0.63-1.60) in Flu/Treo to 1.65 (1.15-2.36) in Flu/Bu with myeloablative dose (Figure 1). Among patients with severe pulmonary disease, significant increases in hazard were seen only in patients treated with myeloablative Flu/Bu and Flu/Mel. In diabetes mellitus, no regimens were clearly associated with increased risk of overall mortality. However, Flu+TBI trended strongly toward increased risk with an HR of 1.55 (1.00-2.41, p = 0.051). Greater comorbidity-associated risk was not consistently associated with increasing conditioning, and the hazards associated with each comorbidity in the MAC and RIC settings were broadly overlapping. Similar trends were seen for the outcome of non-relapse mortality, although statistical significance (p 〈 0.05) was not observed in the setting of low event numbers. Conclusions: These results confirm our hypothesis that comorbidities exert an effect on transplantation outcome in a conditioning regimen-specific manner. Additional study, both retrospective, and prospective, may eventually allow for the precision selection of a conditioning regimen based on the individual patient's physiological status. Disclosures Finke: Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding. Malladi:Roche: Membership on an entity's Board of Directors or advisory committees. Mohty:MaaT Pharma: Consultancy, Honoraria.

Description: Abstract 4489 Introduction: The speed of immune reconstitution post haematopoietic stem cell transplant (HSCT) is important both in terms of post transplant infectious complications and the risk of disease relapse or development of secondary malignancies. It is, therefore, important that immune reconstitution is assessed following the introduction of a new conditioning protocol. Yttrium-90 labelled anti-CD66 has been used in our institution as part of phase I and II clinical trials in both the autologous and allogeneic setting. There is currently, to our knowledge, no published data looking at immune reconstitution post targeted radiotherapy. Patients and methods: 19 patients in our institution have undergone allogeneic HSCT with reduced intensity conditioning and the addition of targeted radiotherapy (both sibling and volunteer unrelated donor). In 18 patients conditioning was with Fludarabine, Melphalan and Campath-1H (one Fludarabine, Cyclophosphamide and Campath-1H). The Yttrium-90 labelled anti-CD66 was shown to add a mean of 35Gy radiation dose to the bone marrow at the highest radiation dose level. 19 control patients were matched as closely as possible for conditioning chemotherapy, underlying disease, prior treatment, age and donor age. Immune reconstitution data are routinely recorded in our institution every three months for the first two years post allogeneic stem cell transplantation. These data were retrospectively collected and analysed for all 38 patients. The p values were calculated using Mann-Whitney tests. Patient characteristics for the two groups are shown below (Table 1). Results: There was no statistically significant difference in the engraftment data between the two groups (Table 2). CD3+, CD4+ and CD19+ results for the two groups are shown in the graphs below: Differences were statistically significant only for CD3+ cells at three and six months post transplant, where levels were higher in the targeted radiotherapy group (p=0.02 and p=0.01 respectively) and at six months for CD4+ cells, where levels were significantly higher in the targeted radiotherapy group (p=0.03). Beyond six months post transplantation no statistically significant difference was seen. No statistically significant difference was seen for B cells at any time point in the first two years. Mean IgG and IgM values were within normal reference ranges for both groups at all time point measured. Donor lymphocyte infusion (DLI) may influence the rate of immunological reconstitution, therefore data regarding DLIs given in the first two years were collected. The control group received slightly more DLIs in the first two years post transplant (a mean of 4.1 compared to 2.8 in the targeted radiotherapy group, p= 0.17) with a mean total CD3+ cell dose of 5.4×106/Kg in the targeted radiotherapy group and 8.3×106/Kg in the control group, p= 0.50. Early Chimerism results (Day 30, 3 months and 6 months post transplant) were also compared, and no statistically significant differences were found. Conclusions: Targeted radiotherapy has great potential for delivering significant doses of radiation to sites of disease without additional toxicity. It appears that the addition of targeted radiotherapy to a reduced intensity conditioning regimen does not adversely affect immune reconstitution post allogeneic stem cell transplantation. Larger patient numbers are required to confirm these findings. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4511 Introduction: The outcome for patients with primary refractory or refractory relapse of acute leukaemia, particularly those with disease present at the time of transplant, remains very poor even using full intensity conditioning schedules. With the aim of improving outcome, we have employed the use of pre-conditioning chemotherapy prior to the delivery of both reduced toxicity (RTC) and full intensity transplants during the subsequent period of cytopenia. Initial results indicate feasibility and efficacy in this poor risk disease. The bi-halogen purine analogue Clofarabine has significant activity as a single agent for the treatment of ALL and AML and is well tolerated, characteristics suggesting Clofarabine is an ideal agent to use in pre-conditioning. Patients and methods: We have treated 11 patients with high-risk, refractory acute leukaemia or advanced myelodysplasia (MDS) using Clofarabine pre-conditioning to reduce disease burden before full intensity or RTC allogeneic transplantation. Patient characteristics for the two groups are shown below (Table 1). Clofarabine was administered as a single agent (40mg/m2/day for 5 days), five received RTC using Busulphan or Melphalan-containing transplant schedules; six full intensity total body irradiation (TBI) based conditioning. Indications for using Clofarabine included severe allergy to Cytarabine, heavy prior exposure to anthracycline or lack of response to other salvage agents. 10 of 11 patients had significant marrow involvement prior to administration of Clofarabine. Results: In this cohort we have not seen additional unexpected complications. One patient who received a RTC regimen, was treated for VOD on clinical suspicion but liver biopsy indicated grade 3–4 haemosiderosis only. Two patients who received TBI-based transplants suffered grade 3–4 mucositis. The extended period of pancytopenia compared with conventional transplant schedules was manageable, with no unexpected infectious complications. The median time to a neutrophil count of 〉 0.5 × 109/l was 18 days post stem cell infusion (range 12–33 days) and to a platelet count 〉 20 × 109/l was 13 days (range 11–32 days). All patients achieved ≥ 98% donor chimerism by day +30. 2 of 11 patients (18%) experienced grade 3–4 acute GvHD (1 cutaneous, 1 gut) which responded to additional immunosuppression. 9 of 10 patients with disease present at the time of Clofarabine achieved substantial bulk reduction or eradication of marrow leukaemic blasts following the Clofarabine. 5 of 11 patients died from disease relapse post allograft at 2–13 months post transplant, including the patient with Clofarabine-refractory disease. 6 patients are currently in CR at 1–77 months follow up. Overall survival for the 11 patients, using Kaplan-Meier analysis, is 48% with a median follow up of survivors of 26 months (range 1–77), shown below in figure 1: Conclusions: The use of Clofarabine as a pre-conditioning agent prior to the administration of the transplant conditioning schedule is well tolerated with both full intensity and reduced toxicity protocols. This approach to allogeneic transplantation shows promise for the therapy of patients with high risk refractory acute leukaemia. Disclosures: Richardson: Genzyme: Advisory board Other, Research Funding. Off Label Use: Clofarabine is licensed for the treatment of relapsed/refractory ALL in paediatric and young adult patients. This paper includes discussion of use in the treatment of AML/high risk MDS for which the drug has orphan drug status in the EU.

Description: Introduction: Prior to effective novel agent (NA) approval for CLL, alloHSCT was recommended for CLL patients (pts) with early relapse/refractory disease after purine-analogs or deletion 17p (del17p) or TP53 mutation (TP53mut) based on expert consensus and retrospectively demonstrated overall survival (OS) advantage. Since 2014, approvals of ibrutinib (ibr), venetoclax (ven), and PI3K inhibitors (PI3Ki) have led to fewer alloHSCT for CLL. While NAs are indisputably effective, many pts will eventually progress through all available NAs. In the absence of data-driven consensus regarding role of alloHSCT for CLL, decision about proceeding to transplant is currently based on disease and transplant risk, response to NAs, and pt preference. This study of CLL pts who underwent alloHSCT following NA therapy (tx) aimed to help define the role of this potentially curative modality in the era of NAs. Methods: This multicenter, retrospective cohort study examined CLL pts who underwent alloHSCT following treatment with ≥ 1 NA, including baseline clinical, prognostic, and transplant characteristics, tx preceding alloHSCT, transplant outcomes, and tx following alloHSCT. Complex karyotype (CK) and CLL status [complete remission (CR), partial remission (PR), stable disease (SD), and progression of disease (POD)] were defined per iwCLL criteria (Hallek, et al. Blood 2018). Univariate analyses utilizing COX regression evaluated association between pre-alloHSCT factors and progression free survival (PFS). PFS, OS, and non-relapse mortality (NRM) were estimated using Kaplan Meier and life table methods. Other statistics were descriptive. Results: 69 pts with CLL underwent alloHSCT following ≥ 1 NA across 14 US and EU centers, including 6 pts with Richter's transformation (RT) prior to alloHSCT. Table 1 describes baseline characteristics. Prior to alloHSCT, 78% received ibr (n=53), 39% ven (n=25), 20% PI3Ki (n=13), and 36% ≥ 2 NAs. 90% (n=62) received a NA immediately preceding alloHSCT [n=32 ibr (16% CR, 75% PR, 9% SD/POD), n=25 ven (52% CR, 40% PR, 8% SD/POD), 4 PI3Ki (75% PR, 25% SD/POD), 1 IMiD]. With a median (med) follow up 28 months (mo; range 1.2 -85), med PFS and OS from alloHSCT for the entire cohort were not reached (Figure 1A, B). PFS and OS for pts with CLL (excluding RT pts) from alloHSCT were 60% and 82% at 24 mo respectively. Poor risk disease characteristics (TP53mut, del17p, CK), prior NA exposure (ibr, ven, PI3Ki, ≥2 NAs), and transplant characteristics (matched (8/8) vs. mismatched (

Description: Introduction Hematopoietic growth factors including G-CSF are manufactured by the use of recombinant technology. When biologically equivalent agents are manufactured they are termed “biosimilars”. The use of biosimilars in general and in particular for peripheral blood hematopoietic stem cell (PBSC) mobilization has stimulated an ongoing debate regarding their efficacy and safety. The use of biosimilar G-CSF (Ratiograstim®, Tevagrastim®, Biograstim®, Zarzio®, Nivestim®) was approved by the European Medicines Agency (EMA) for all the registered indications of the originator (Neupogen®) including mobilization of stem cells. Methods We performed a comprehensive review of published reports on the use of biosimilar G-CSF covering patients with hematological malignancies as well as healthy donors that underwent stem cell mobilization with a biosimilar G-CSF for autologous and allogeneic stem cell transplantation, evaluating mobilization yield and safety profile as well as engraftment and transplantation outcome. Results An extensive literature review produced 903 patients mostly with hematological malignancies as well as healthy donors that underwent successful autologous or allogeneic stem cell mobilization respectively using a biosimilar G-CSF (Ratiograstim®/Tevagrastim® or Zarzio®). A total of 519 patients or donors underwent stem cell mobilization with Ratiograstim®/Tevagrastim®, while 384 patients or donors underwent stem cell mobilization with Zarzio®. The indication for stem cell mobilization in hematology patients included 326 with multiple myeloma, 273 with Non-Hodgkin’s lymphoma (NHL), 79 with Hodgkin’s lymphoma (HL), and others. 155 sibling or volunteer unrelated donors were mobilized using either Ratiograstim®/Tevagrastim® or Zarzio®. Biosimilar G-CSF based stem cell mobilization for both autologous and allogeneic transplantation resulted in good mobilization of CD34+ stem cells with side effects similar to reference G-CSF. Post transplantation engraftment did not significantly differ from results previously documented with the originator filgrastim (Neupogen®) in historical controls. The side effects experienced by the patients or donors mobilized by biosimilar G-CSF were minimal and were comparable to those of originator G-CSF. (More detailed results regarding yield, engraftment and side effects will be disclosed in the conference.) Conclusions In summary, we present the published experience for the use of biosimilar G-CSFs in more than 900 patients and normal family related and volunteer unrelated donors. Both the toxicity profile PBSC yield and efficacy seem equivalent to historical data with the reference G-CSF. Until results from multi-center randomized clinical trials that directly compare biosimilar G-CSF with the originator G-CSF are reported, it is important to collect and summarize all of the available clinical experience in order to allow the transplant community to make informed decisions regarding the choice of G-CSF. Disclosures: Schmitt: AMGEN: Honoraria; Teva: Consultancy, Honoraria, Research Funding, Travel Grant, Research Grants Other. Publicover:Teva: Travel Grants, unrestricted educational grant Other. Orchard:Teva: Honoraria, Travel Grants, research grants Other. Schmitt:TEVA: Travel grant Other. Nagler:Teva: Honoraria, Travel grants, research grants Other.

Description: Introduction: Qualitative and quantitative deficiencies in T-cell mediated immunity following allogeneic hematopoietic stem cell transplantation (HSCT) are associated with a high incidence of cytomegalovirus (CMV) infection, which remains an important cause of morbidity and cost, and contributes to mortality. Adoptive cellular therapy (ACT) can potentially expedite reconstitution of CMV-specific immunity and improve outcomes post HSCT. A number of uncontrolled studies have demonstrated proof of concept for such strategies. Previously we presented data from a randomized controlled trial assessing the effect of CMV-specific ACT (Cytovir CMV™) on immune reconstitution following unrelated donor HSCT (CMV~ASPECT). Now we report on a randomized controlled trial to evaluate the incidence of CMV reactivation and safety in a larger cohort of related donor HSCT patients treated with CMV-specific ACT. (CMV~IMPACT: ClinicalTrials.gov NCT 01077908). Methods: The study enrolled CMV-seropositive patients 〉16 years old, undergoing T-cell depleted (alemtuzumab) HSCT from a matched sibling CMV-seropositive donor, in 14 UK transplant centers. Patients and donors were selected using standard criteria. Patients were randomized into either ACT or control arms. CMV-specific cells were manufactured from a dedicated donor apheresis by direct selection at a central facility using either a StreptamerTM or gamma-capture technique (CliniMACS® Cytokine Capture System, IFN-gamma). Products were manufactured using Streptamers if the donor expressed a suitable HLA allele, or using gamma-capture if not. The 14 patients receiving the latter product are not included in this preliminary analysis. CMV surveillance was performed using quantitative PCR. All groups received standardized antiviral pre-emptive treatment. Cells were cryopreserved at a maximum dose of 5x104CD3+/kg and administered to the patient on day 27/28 post-transplant, regardless of CMV surveillance results (prophylactic administration). Patients with ≥ grade 2 acute GvHD or systemic steroid administration at baseline (D27/28) were withdrawn. Patients were assessed for CMV reactivation based on blinded retrospective assessment by the Chief Investigator. Patients were also assessed for evidence of GvHD and CMV-specific immune reconstitution. Results: As of August 2014, all but one patient had completed the study. There were no clinically apparent differences in serious adverse event (SAE) or acute GvHD events between the two arms. Notably, the number of patients experiencing 〉1 treatment episode was considerably lower than had been predicted in the control group (26% vs 60% predicted). There were fewer CMV reactivations in the ACT arm compared to the control arm (0.75 vs 1.0/patient), and fewer patients experiencing 〉1 treatment episode (15% vs 26%), although neither reached statistical significance. There was a trend toward reduced overall treatment duration in the ACT arm (Table 2, p=0.14). Preliminary data are summarized below. A complete and final analysis will be available at the time of the conference. Table1: Patient Disposition/Safety ACT Control Enrolled (withdrawn prior to baseline visit) Safety set Per protocol set (no ACT administered in 10 randomized patients) 40 (10) 30 20 35 (4) 31 31 Reasons for withdrawal · GvHD or steroids at baseline · Other 2 8 2 2 No. (%) with new onset acute GvHD (safety set; 100 day follow up) 2 (6.7) 1 (3.2) No. (%) with at least 1 SAE (safety set) 12 (40.0) 10 (32.3) Table2: Duration of CMV Treatment (days; per protocol set) ACT (n=20) Control (n=31) p Mean (stdv) 19.1 (27.8) 27.3 (31.3) 0.14 Median (min:max) 11 (0 : 114) 25 (0 : 133) Conclusions: In this randomized trial of CMV specific T-cells post-HSCT, adoptive cell therapy (Cytovir CMV™) was not associated with a significant increase in safety events, and preliminary analysis indicates Cytovir CMV administration may be associated with lower rates of CMV reactivation and shorter durations of viral treatment, though the lower than predicted reactivation rate in the control group reduced the power of the trial to demonstrate this at a statistically significant level. Disclosures Cobb: Cell Medica Ltd: Employment. Newton:Cell Medica Ltd: Employment. Thomas:Cell Medica Ltd: Employment. Moss:Cell Medica Ltd: Membership on an entity's Board of Directors or advisory committees.

Description: The occurrence of late events [i.e. secondary malignancies (SM)] after therapy is of special relevance in patients with Hodgkin«s lymphoma (HL) as the median age of this population is quite low and first line therapy is curative in a high proportion of them. Autologous stem cell transplantation (ASCT) is the standard of care for patients with HL in first relapse and chemosensitive disease and for those patients who demonstrate to be primary refractory. The administration of chemotherapy +/- radiotherapy is a risk factor for the development of SM and, high dose chemoradiotherapy given as conditioning regimen before stem cell infusion can further increase this risk. In this retrospective study we have analyzed the incidence of SM as well as of the different subtypes [acute leukemias (AL) / myelodisplastic syndromes – myeloproliferative disorders (MDS-MPD), lymphomas and solid tumors (ST)] in more than 2000 HL patients undergoing an ASCT with a very long follow up after transplantation. 2261 patients with HL being treated with an ASCT between January/1985 and December/1995 and reported to the Lymphoma Database of the EBMT have been included in this analysis. There were 871 (38.5%) females and 1390 (61.5%) males with a median age at diagnosis of 26.8 years and at transplantation of 30.2 years. Median follow up for surviving patients was 9.1 years. Median time from diagnosis to ASCT was 26.6 months and 1989 patients (88% of the series) received at least 2 lines of chemotherapy before undergoing the autologous procedure. 694 patients were autografted in complete remission (CR) and the remaining 1567 with visible disease (amongst them, 279 patients had primary refractory disease, 458 patients sensitive relapse and 216, refractory relapse). Total body irradiation (TBI)-containing regimens only represented 4.2% of all conditioning protocols. 1300 patients were conditioned with BEAM / BEAM like protocols, 670 with CBV and 197 with other combinations. As expected because of the year of transplantation, bone marrow was used as the source of stem cells in 1407 patients (62.2%). After a median follow up of 10.5 years for all patients, 978 (45.4%) are alive and 1178 (54.6%) have died, 959 patients (43.7%) have relapsed after ASCT and 378 (17.5%) have died of non-relapse mortality (NRM). Relapse rate (RR) of the whole population of patients was 43.5%, 46.2% and 47% at 5, 10 and 15 years, respectively. NRM ranged from 14.6% to 19.8% at 5 and 15 years after ASCT, respectively. Disease free survival (DFS) was 41.9%, 36.5% and 33.2% at 5, 10 and 15%, respectively and finally, overall survival (OS) at 5, 10 and 15 years was 53.1%, 44.4% and 38.8%, respectively. 122 patients (5.4% of the series) developed a SM after ASCT. The most frequent ones were ST (49 patients – 40.2% of the series) followed by AL / MDS-MPD (26 patients – 21.3% / 23 patients – 18.8%), lymphomas (17 patients – 11.5%) and others (9 patients – 7.4%). 95 patients (78%) were in CR at the time of developing the SM and 27 patients (22%) had already relapsed after ASCT and being treated with additional chemotherapy. 30 patients with SM died of this late effect after ASCT (3% of NRM for the whole population of patients). In conclusion, the development of a SM after an ASCT represents a significant late effect in this big population of HL patients with a very long follow up, the most frequent ones being the ST that, as expected seem to develop later after transplantation than AL / MDS – MPD and lymphomas. The impact of prior therapy as well as other well know prognostic factors in the development of SM after ASCT is still unclear and needs to be better defined.SMSTAL / MDS - MPDLymphomas5-year CI2.4%0.3%1.7%0.1%10-year CI4.8%1.4%2.2%0.3%15-year CI7.7%3.2%2.5%0.4%20-year CI11.7%5.9%2.7%1.5%CI. Cumulative Incidence Disclosures: No relevant conflicts of interest to declare.