Post allo-SCT Research Articles

ANTIBODY RESPONSES AND SAFETY OF THE COMMERCIALLY AVAILABLE VACCINES AGAINST SARS-COV-2 VIRUS IN ALLOGRAFTED PATIENTS: REAL WORLD DATA FROM A SINGLE CENTER

ObjectivePatients (pts) who have undergone allogeneic stem cell transplantation (alloSCT) are at high-risk for life-threating complications post SARS-CoV-2 infection, and the mortality rates has been reported of approximately 30-35%. The currently available vaccines proved their effectiveness in the general population by reducing the severity of the COVID-19 infection however, scant data exist regarding the safety and efficacy of the commercially available vaccines in allografted pts.MethodologyAfter a median of 2,7 (0,3-6,7) ys post alloSCT, 20 pts received within a median of 42 days, 2 vaccines of either Pfizer (n=17) or combinations of Pfizer with Moderna (n=2) or AstraZeneca (n=1). Off immunosuppression without evidence of active GvHD were 14 pts, 1 was only on Cyclosporine (CSP) while 5 were on steroids plus CSP or MMF or Ibrutinib for GvHD treatment. Automated commercial chemiluminescence immunoassay (CLIA) against spike (S1/S2) protein was used for antibody responses detection.ResultsDuring vaccination program no side effect grade ≥3 (including allergy, thrombosis, heart dysfunction or laboratory abnormalities) was reported. The commonest complains were fatigue (20%), bony pain (10%) and fever <38.5 oC (10%). Satisfactory antibody responses were observed in 66% and 95% of pts after the 1st and 2nd dose respectively. Importantly, active GvHD and intensive immunosuppression, did not negatively affect the antibody responses. None of the vaccinated pts developed COVID infectionConclusionOur retrospective study although with small number of patients and with short term follow-up, in agreement with others, confirms that the current commercially available vaccines against SARS-CoV-2 are safe and highly effective in producing effective humoral responses in allografted patients. Prospective studies with longer follow-up are needed to elucidate the proper timing and the number of necessary doses for a safe and effective approach in preventing severe COVID-19 infection

Non-relapse cytopenias following allogeneic stem cell transplantation, a case based review.

The development of non-relapse cytopenias (NRC) is a relatively common occurrence post allogeneic stem cell transplant (alloSCT). Whilst there have been attempts to classify post alloSCT cytopenias by transplantation groups, ambiguity of definitions in prior publications compounded by a lack of availability of high-quality evidence, provide challenges to clinicians attempting to manage these complex patients. In this review we describe 3 cases of NRC, (1) Graft Failure with graft rejection representing cytopenias with minimal donor chimerism (2) Poor Graft Function representing cytopenias with complete donor chimerism and (3) Cytopenias with mixed donor chimerism. This case-based review will evaluate the currently available evidence regarding the pathophysiology of each entity as well as the evidence for current therapies with the aim of providing guidance to clinicians managing these complex patients.

P1351: CHARACTERIZING ALLOGENEIC STEM CELL TRANSPLANTATION SAFETY IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES AFTER PEMBROLIZUMAB THERAPY

Background: Although allogeneic stem cell transplantation (allo-SCT) and programmed cell death 1 (PD-1) blockade have separately shown efficacy in some lymphoid malignancies, the safety of allo-SCT after anti–PD-1 therapy in these patients remains a high clinical interest. Aims: We present data from an analysis from 4 KEYNOTE phase 1-3 studies to describe predetermined complications in patients who received allo-SCT following pembrolizumab therapy. Methods: The analysis included patients from the KEYNOTE-013 (NCT01953692, n=20), KEYNOTE-087 (NCT02453594, n=31), KEYNOTE-170 (NCT02576990, n=5), and KEYNOTE-204 (NCT02684292, n=14) trials who have a known allo-SCT transplantation date received within 2 years of the last dose of study pembrolizumab. Descriptive statistics were used for predefined post–allo-SCT complications of interest. The cumulative incidence of acute grade 2-4 graft-versus-host disease (GVHD), acute grade 3-4 GVHD, and chronic GVHD was estimated. The corresponding competing risk events were death without acute grade 2-4 GVHD, death without acute grade 3-4 GVHD, and death without chronic GVHD, respectively. The cumulative incidence of post–allo-SCT transplant-related mortality (TRM) was estimated with relapse as a competing risk. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Seventy patients were included in the analysis. Median age was 30 y (range, 18-65), 57 (81.4%) had classical Hodgkin lymphoma (cHL), and the rest had non-Hodgkin lymphoma. 69 of 70 (98.6%) patients received pembrolizumab monotherapy; 1 patient received pembrolizumab + lenalidomide. Median duration on study treatment was 5.3 months (range, 0.7-29.6) and median time from last pembrolizumab dose to first allo-SCT was 4.6 months (range, 1-20). Before transplantation, 49 patients (70.0%) had intervening anticancer regimen; 34 (48.6%) had active disease, 31 patients (44.3%) were in remission at time of transplant, and 5 patients (7.1%) had unknown disease status. Overall, 55 patients (78.6%) developed GVHD (acute, 38; chronic, 17). The estimated 6-month post–allo-SCT cumulative incidence was 0.41 (95% CI, 0.30-0.53) for grade II-IV acute GVHD and 0.20 (95% CI, 0.12-0.30) for grade III-IV acute GVHD; 1 year post–allo-SCT was 0.21 (95% CI, 0.12-0.31) for chronic GVHD. Other predetermined complications, including critical illness, immune-mediated adverse events, pulmonary complications, and veno-occlusive liver disease, occurred in 32 patients (45.7%). After a median follow-up (defined as the time from allo-SCT to data cutoff) of 40.1 months (range, 5.1-71.2), the post–allo-SCT median PFS was not reached (NR) (95% CI, 14.5-NR) and the 30-month post–allo-SCT PFS rate was 56.8% (95% CI, 42.9-68.5) (Figure A); median OS was NR (95% CI, NR-NR) and the OS rate at 12 months was 82.2% (Figure B). The estimated post–allo-SCT cumulative incidence for TRM at 6 months was 0.09 (95% CI, 0.03-0.17) and for relapse at 26 months was 0.27 (95% CI, 0.16-0.38). PFS and OS outcomes were comparable in the subgroup of patients with cHL. Image:Summary/Conclusion: The incidence of GVHD in this population is comparable to historical data (40%-80% and 30%-70%, respectively). The incidence of severe acute GVHD may be higher than a typical modern allo-SCT series, although TRM was low. The observed PFS and OS outcomes compare favorably to historical benchmarks (2-year PFS ranging from 45%-48%; 1-year OS >80%). Altogether, this analysis lends confidence that allo-SCT is feasible for patients with lymphoid malignancies after PD-1 blockade.

The new generation tyrosine kinase inhibitor improves the survival of chronic myeloid leukemia patients after allogeneic stem cell transplantation.

The introduction of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) treatment has dramatically improved the prognosis of CML patients and reduced the number of patients receiving allogeneic stem cell transplantation (allo-SCT). However, the impact of the newest-generation TKIs on the overall survival (OS) after allo-SCT has not been well described. To investigate the beneficial effects of TKIs on the prognosis after allo-SCT, we conducted a retrospective observational study using the Transplant Registry Unified Management Program database in Japan. We analyzed 1188 patients (male/female: 738/450; median age: 44years; range: 16-75) who underwent their first allo-SCT between January 2001 and December 2018. We divided the patients into two groups according to the TKI treatment used before allo-SCT: group 1 was treated with the first generation TKI imatinib; group 2 was treated with the second generation TKIs nilotinib, dasatinib, or bosutinib and/or the third generation TKI ponatinib. We compared the post allo-SCT OS between the two groups. The 3-year OS rates (95%CI) of groups 1 and 2 were 59.3% (54.8%-63.5%) and 65.8% (61.6%-69.6%), respectively (p=0.017). Multivariate analysis confirmed that group 2 had superior OS after allo-SCT compared to group 1 (p=0.002). Other factors associated with superior prognosis were age ≤65, performance status (PS) 0/1, a 6/6 HLA-matched donor and chronic-phase (CP) disease status at allo-SCT. A subgroup analysis showed poor prognoses for patients who could not obtain a molecular response before allo-SCT and patients with positive T315I mutation in the BCR/ABL gene. In group 2, early allo-SCT was correlated with superior OS in patients with a blast-crisis disease status at allo-SCT (p=0.001). The cumulative incidence of non-relapse mortality rate significantly decreased in group 2 (p=0.0005). The post allo-SCT OS was improved both by pre- and post-management of allo-SCT and by the introduction of newer TKIs.

COVID-19 Vaccination after Allogeneic Stem Cell Transplantation: Real Word Data on Safety and Efficacy. a Single Center Experience.

IntroductionDifferent vaccines have been recently approved by FDA and EMA for the prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, demonstrating a protection rate ranging from 60% to almost 95% in phase II/III trials. Immunocompromised patients, including those undergoing allogeneic stem cell transplantation (allo-SCT), were excluded from vaccine trials. While EBMT recommended the vaccination for transplanted patients, data concerning efficacy and safety in this particular setting are scarce. Since infections represent a relevant cause of transplant-related mortality and the treatment and management of SARS-CoV-2 infection in allo-SCT patients proved to be challenging and complex, we prospectively evaluated the safety and the development of protective response against SARS-CoV-2 vaccines in our allogeneic transplanted patients.Materials and MethodsStarting in March 2021, allogeneic stem cell transplanted patients with different hematological diseases underwent COVID-19 vaccination. Taking into account the EBMT recommendations, we considered patients suitable for vaccination when (1) they were at least 3-6 months after allo-SCT, (2) didn't have any graft versus host (GvHD) activity, and (3) received less than 0,5 mg/kg steroids as part of the immunosuppressive treatment. There was no recommendation for a specific type of vaccine, with the only exception for life-attenuated vaccines, which are mostly contraindicated in the post allo-SCT setting. Vaccinated patients were regularly monitored for the potential development of adverse events. The anti-SARS-CoV-2 Spike protein antibodies were measured in blood samples to assess the humoral response. In case of no response with undetectable anti-Spike antibodies 2 week after the second dose of vaccine, we repeated the measurements at regular intervals until week + 6-8 after the completion of vaccination. Patients with no measurable antibodies 8 weeks after completion of the vaccination were considered as no responders.ResultsBetween 03/2021 and 06/2021 a total of 83 patients underwent COVID-19 vaccination (including first and second dose) during the post allo-SCT follow-up. Patients' characteristics are listed in Table 1. Most patients (77%) received BNT162b2, while only a small subgroup (8%) underwent a mixed vaccination after a first dose of ChAdOx1-S. We considered the mixed vaccination mostly to maximize the response. Overall, the two vaccine doses were well tolerated, with only 5% of patients developing a reactivation of GvHD. No relevant grade 3 or 4 organ toxicities were observed. Overall, 66% of patients in our cohort showed a humoral response. The incidence of positive serology was lower in patients who underwent the vaccination within the first 18 months after allo-SCT (29% vs 83% for patients >18 months after allo-SCT, p< 0.001). In multivariate analysis other risk factors that were associated with poor or no response were lack of immune reconstitution (p< 0.001) and ongoing immunosuppressive therapy (p= 0.009). The age of patients at the time of vaccination, sex, intensity of conditioning regimen and the use of ATG did not prove to have an influence for a humoral response during the post-transplant follow up.DiscussionThe achievement of a protective immunity against SARS-CoV-2 represents a crucial event for a frail population, like allogeneic stem cell transplanted patients. So far and to our knowledge little is known about the safety and efficacy of the COVID-19 vaccination in this particular setting. Here, we report one of the first series of patients undergoing COVID-19 vaccination after allo-SCT. We demonstrated that a humoral response can be achieved, especially for those patients who are in the long-term follow-up, underwent immune reconstitution and are free from immunosuppressive drugs. For the other patients, who represent the frailer subgroup, in the absence of a documented immune response after 2 doses of vaccine, the option of a third dose in order to increase the probability of response should be evaluated in prospective clinical trials. [Display omitted] DisclosuresViardot: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; University Hospital of Ulm: Current Employment; Amgen: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Döhner: Roche: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Ulm University Hospital: Current Employment; Abbvie: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Pfizer: Research Funding; Berlin-Chemie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; GEMoaB: Consultancy, Honoraria. Sala: Novartis: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Jazz: Consultancy, Honoraria.

Romidepsin in Conditioning and Maintenance Mitigates Relapse Risk and Enhances NK-Cell Cytotoxicity in Patients Receiving Allogeneic Stem Cell Transplant for Aggressive T-Cell Malignancies: Results of a Phase I/II Clinical Trial

Romidepsin in Conditioning and Maintenance Mitigates Relapse Risk and Enhances NK-Cell Cytotoxicity in Patients Receiving Allogeneic Stem Cell Transplant for Aggressive T-Cell Malignancies: Results of a Phase I/II Clinical Trial

Allogeneic Transplantation in Fit Older Adults Is Feasible and Encouragingly Efficacious. Post Remission Data from the Prospective ECOG-ACRIN (E2906) Clinical Study

Allogeneic Transplantation in Fit Older Adults Is Feasible and Encouragingly Efficacious. Post Remission Data from the Prospective ECOG-ACRIN (E2906) Clinical Study

Richter transformation of chronic lymphocytic leukaemia: a British Society for Haematology Good Practice Paper.

Richter transformation of chronic lymphocytic leukaemia: a British Society for Haematology Good Practice Paper.

Selinexor Maintenance Is Feasible and Tolerable after Allogeneic Stem Cell Transplant (allo-SCT) for Patients with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Background: Selinexor, an exportin 1 (XPO1) inhibitor, has demonstrated anti-leukemic effects as a single agent in relapsed/refractory AML. We hypothesized that selinexor could be used as maintenance therapy after allo-SCT to prevent disease relapse in patients with AML and MDS.Methods: This phase I trial tests selinexor as a maintenance therapy in patients with AML/MDS undergoing allo-SCT (NCT02485535). The primary endpoint was to determine the maximum tolerated dose (MTD) of selinexor after allo-SCT. Patients were enrolled between day 60 to day 100 post allo-SCT if there was no GVHD or disease relapse. Once weekly oral selinexor started approximately 100 days post allo-SCT, and continued for 12 months if tolerated, and there was no relapse of disease. Dose limiting toxicity (DLT) was defined as any grade 3 or higher treatment-related adverse event (AE) that occurred within the first treatment cycle (28 days).Results: From January 2016 to March 2017, nine patients were enrolled including seven with AML and two with MDS. Selinexor dose levels were 60mg weekly (n=6) and 80mg weekly (n=3). Per stem cell transplant disease risk index (DRI), three patients had high risk and five had intermediate risk. Six patients with AML entered allo-SCT in CR (five CR1, one CR2) and one patient had refractory AML. Two MDS patients had active disease at the time of transplant. Four patients had matched related donors (MRD), two had matched unrelated donors (MUD), and three had haplo/cord SCT. One patient had myeloablative conditioning, and eight had RIC. The median time from allo-SCT to first dose of selinexor was 97 days (range: 66-102). One of the first three patients treated at 60mg weekly developed grade 3 nausea, thus three more patients were enrolled to the 60mg weekly dose level. After no additional DLTs at 60mg weekly, patients were enrolled to 80mg weekly dose level. While there was no DLT during the first cycle treatment at 80mg weekly, the dose of selinexor was decreased to 60mg weekly at the beginning of cycle 2 due to decreased chimerism in one patient and in one in cycle 3 due to neutropenia; one patient stopped treatment in the middle of cycle 2 due to leg cramping. The MTD of selinexor post allo-SCT was determined to be 60mg weekly. The most common AEs were fatigue (67%), anorexia (56%), nausea (56%), vomiting (33%) and diarrhea (22%) which were grades 1-2 with the exception of one case of grade 3 nausea. These AEs were manageable with adequate supportive care, including ondansetron, dexamethasone, megestrol and short hold of drug. One patient is finishing 12 months of treatment without major complications. One patient developed grade 1 skin GVHD during tapering immunosuppression not related to selinexor, and 2 patients developed skin and/or liver GVHD after donor lymphocyte infusion (DLI) for low chimerism, which was not related to selinexor. With median follow-up of 359 (219-639) days from transplant, two patients had disease relapse after 2 and 4 cycles of treatment, of which one patient died from disease progression. Three patients are still on treatment, three patients are off study due to tolerability (Neutropenia=1, fatigue=1; and leg cramping=1), and one patient is off study due to liver GVHD after donor lymphocyte infusion (DLI). The median remission duration from the start of Selinexor treatment was 199 (59-542) days. Correlative studies for MRD monitoring and immune reconstitution are on-going.Conclusions: Selinexor maintenance after allo-SCT is feasible and tolerable without increased risk of GVHD. The recommended phase II dose of selinexor maintenance post allo-SCT is 60mg weekly. Additional patients are being enrolled to the expansion cohort at the dose of 60mg weekly for better understanding of the toxicities and efficacy. DisclosuresLiu:BMS: Research Funding; Karyopharm: Research Funding. Larson:Daiichi Sankyo: Consultancy, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Research Funding; Astellas: Consultancy, Research Funding. Stock:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy.

Sequential Regimen with Thiotepa, Cyclophosphamide, Etoposide, Fludarabine and Busulfan in Allogeneic Stem Cell Transplantation for the Treatment of Relapsed and Refractory Hematological Malignancies

INTRODUCTION: Relapsed / Refractory leukemia and lymphoma (R/R, L/L) patients have a very poor prognosis despite all the well-known therapeutic strategies. Sequential conditioning followed by allogeneic stem cell transplantation (allo-SCT) provides an efficient disease control in those high risk patients.PATIENTS AND METHODS: we conducted a retrospective study at the American University of Beirut medical center (AUBMC) to assess the safety and efficacy of sequential conditioning in patients with R/R, L/L undergoing allo-SCT. We included 14 consecutive patients with (R/R, L/L) who received sequential conditioning followed by allogeneic stem cell transplantation (allo-SCT) from either matched related or haploidentical donors from April 2015 to May 2017. At time of transplantation patients included in the study were either in progressive disease (PD) or complete remission 2 (CR2), or partial remission (PR) after many lines of treatment. The study was approved by the institutional review board of American University of Beirut Medical Center. All patients received the following conditioning regimen of sequential chemotherapy: Thiotepa intravenous (IV) (5mg/kg/day) on days -13 and -12, Cyclophosphamide IV (400mg/m2/day) from day -11 to day -8 , Etoposide IV (100mg/m2/day) from day -11 to day-8, Fludarabine IV (30mg/m2/day) from day -5 to day-1, Busulfan IV (130mg/m2/day) on days -5 and -4 and ATG (thymoglobuline) IV 2,5 mg/kg on days -2 and -1 , followed by peripheral stem cells infusion on day 0. All patients characteristics, infectious complications and outcomes are listed in Table1.The primary outcomes weresafety and efficacy of this new sequential conditioning in allo-SCT. Secondary outcomes included engraftment, chimerism, acute and chronic graft versus host disease (GVHD), infections and relapse on days +30, +100 and 1 year post allo-SCT.RESULTS: After a median follow up of 7 months (range, 2-23) post-allo-SCT, all patients had neutrophil engraftment after a median time of 14 days (range, 10-20), and 13 patients had platelets engraftment after a median time of 15 days (range, 10-100). One patient failed to have platelets engraftment. At the time of last follow up, 9 patients (64%) were alive with complete remission (CR), with a median follow up of those of 7 months (range,2-23); four of whom had progressive disease (PD) at time of transplantation. Five patients who had PD at time of transplantation died. Of those, three (21%) died due to disease relapse that occurred at a median time of 152 days post allo-SCT (range, 60-296). The other two (14%) patients died because of transplant related mortality, one because of veno occlusive disease and one because of infection while were in CR. The cumulative incidence of Grade II-IV acute GVHD was 21%. Three patients (21%) developed chronic GVHD. The median progression free survival (PFS) and the median overall survival (OS) were not reached. All the complications and outcomes post allo-SCT are listed in table 1.CONCLUSIONS: Our results indicate that this sequential conditioning regimen appears to be feasible, with low TRM, allows high rate of engraftment and good disease control among high-risk patients. Further large prospective trials needed to evaluate that. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Dose Escalation Prophylactic Donor Lymphocyte Infusion (pDLI) after T-Cell Depleted (TCD) Matched Related Donor (MRD) Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) Is Feasible and Results in Higher Donor Chimerism, Faster Immune Re-Constitution and Prolonged PFS

Background:Alemtuzumab based TCD allografts allow low rates of acute and chronic GVHD. However, delayed immune reconstitution and mixed donor chimerism (MDC) may increase infection rates, if not relapse. We conducted a prospective trial exploring the feasibility of early withdrawal of immunosuppression (WOI) followed by dose-escalation pDLI after alemtuzumab-based TCD conditioning for patients (pts) with high-risk hematologic diseases.Methods:High-risk hematologic malignancies were eligible if planned for matched related or matched unrelated donor TCD allografts and tacrolimus for GVHD prophylaxis. Patients began WOI as early as day 60 if no GVHD or relapse, followed by escalated doses of pDLI every 4-8 weeks for up to 5 treatments starting at 2x105 CD3/kg for MRD and 1x105 for MUD with half-log dose escalation. The primary aim was for over 50% of patients to receive at least one DLI.Results:75 patients (pts) thus far have been enrolled. A planned interim analysis of 59 pts demonstrated that very few MUD allografts were evaluable since it was not possible to achieve WOI and at least one DLI; thus, MRD grafts were primarily enrolled thereafter. In total, 46 pts (61%) received MRD. 37 pts (49.3%) had AML, including 16 (42%) not in remission. Pts received fludarabine/melphalan (n=47), flu/busulfan (n=26), or TBI/etoposide (n=2) with alemtuzumab 30-100mg.40 pts (53%) did not undergo WOI due to acute GVHD (n=16), relapse (n=9), death (n=8), too early for WOI (n=2), poor graft function (n=2) or were enrolled to another study (n=3), and 5 (6.6%) underwent WOI but did not receive pDLI due to acute GVHD (n=4), death (n=1). Successful WOI and receipt of at least one pDLI was achieved in 30 (39.5%) pts, with 4, 9, 5, 5, and 7 pts receiving 1, 2, 3, 4 and 5 total pDLI, respectively. 61.9% (26/42) of MRD patients could undergo WOI and at least one pDLI versus only 14.2% (4/28) of MUD patients. Median time from transplant to first pDLI was 97 days (range 84 to 164). After pDLI, 11 pts developed grade I-IV aGVHD. Rates of aGVHD, grades II-V at 1 year post-HCT were 47% for all pts versus 27.5% for those receiving at least one pDLI. One year NRM rate was 16.7% in all pts and 3.5% in pDLI pts. Median PFS and OS for all pts were 322 days and 644 days, respectively. The median PFS and OS for those receiving at least one pDLI were not reached. 2 year PFS and OS for all the patients were 36.8% and 45.3% compared to 52.5% and 60.7% for patients who received at least one pDLI. At one year, among pts receiving at least one pDLI , 95% of evaluable pts (20/21) had full donor chimerism compared to 59% (10/17) of those not receiving any pDLI. There was also a clear increment in chimerism with each pDLI. Pts receiving pDLI had faster lymphocyte count recovery and higher IgG levels at one year post allo-SCT. Minimal residual disease was monitored by WT1 qRT-PCR in 16 AML/MDS pts who received pDLI; 11/16 (69%) pts had WT1 transcript decrease, which suggests a better outcome for those treated with pDLI. TCR sequencing was done in 8 pts who received between 2-5 pDLI to assess if pDLI could change T cell clonality, resulting in enrichment of possible leukemia-antigen associated T cell proliferation, TCR sequencing using peripheral blood revealed reduction in the TCR diversity and clonal enrichment of T cells. Direct comparison of the outcomes between our historical control pts and the pts treated with pDLI having the same disease risk index (DRI) is ongoing with the hope to provide more definitive PFS benefit using early WOI and pDLI.Conclusions:This prospective trial demonstrates that early WOI followed by dose-escalation pDLI is feasible after alemtuzumab based regimens for matched related donors and may suggest favorable results mediated by improved donor chimerism. For matched unrelated donors, WOI should occur later and/or pDLI given prior to tapering immune suppression. DisclosuresPark:OncoTherapy Science, Inc.: Consultancy. Stock:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Larson:Amgen Inc.: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas: Consultancy, Research Funding. Odenike:Jazz: Membership on an entity's Board of Directors or advisory committees; CTI/Baxalta: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees. Riedell:Kite Pharma: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Liu:BMS: Research Funding; Karyopharm: Research Funding.

Graft Failure Post Allogeneic Stem Cell Transplant: Conditioning Regimen Improves Engraftment and Survival

▪Introduction- Untreated Graft Failure (GF) post allogeneic stem cell transplant (allo-SCT) is potentially lethal. Salvage stem cells with or without additional conditioning regimen can be curative but concerns about toxicity and the need for adequate immunosuppression needs to be balanced in the therapeutic decisions. Due to the rarity of GF and paucity of data no consensus exists on the most preferred combinations to opt at the time of intervention. To address this unmet scenario we performed a large single institution retrospective study.Methods- From January 1996- February 2016, 97 patients received treatment for GF following an allo-SCT. We excluded from the analysis patients (n-15) who received autologous cells as their sole rescue and those who developed GF after progression of the underlying malignancy. Both primary GF (48%) and secondary GF (52%) post 1st allo-SCT were included. Median time from 1st allo-SCT to GF rescue intervention was 56 (range 21-738) days. Conditioning regimen prior to allogeneic rescue cell infusions was categorized as : 1) no preparative regimen (21%) 2) single agent antithymocyte globulin (ATG) or Campath (6%) 3) Reduced intensity conditioning (RIC) chemotherapy or low dose total body irradiation (TBI) (200cGY) (28%) (4) Fludarabine (Flu) + ATG (41%) and 5) miscellaneous other combinations (4%). Engraftment (absolute neutrophil count ≥ 500 for 3 consecutive days) and overall survival (OS) from the time of intervention were the main outcomes of interest. The following factors were considered for their association with primary outcomes following GF rescue intervention: 1) donor/ patient demographics, 2) disease status, 3) graft- source (related, unrelated donors, peripheral blood, bone marrow and umbilical cord blood), cell dose, graft modification (t cell deplete vs replete), level of human leucocyte antigen (HLA)/ABO matching between donor and recipient and 4) treatment related metrics (conditioning regimens and graft versus host disease prophylaxis).Results- Among patients (n=82) who received GF rescue intervention, 56 (68%) engrafted, 10 (12%) failed to engraft and 16 (20%) had early death (< 28 days). With a median follow up of 61 (range 11-242) months, 5-y OS was 18%. Only conditioning regimen correlated with engraftment with a significantly higher proportion of patients engrafting after Flu/Mel (92%) or TBI (91%) based preparative regimens (Table 1). In comparison, 38%, 40%, 67%, and 33% engrafted following no preparative regimen, and conditioning with ATG or Campath, Flu/ATG, and miscellaneous other group, respectively. Change of donor, graft source and graft modification were not significant predictors for engraftment. On multivariate Classification and Regression Tree (CART) analysis, use of 1 HLA antigen mismatched related or unrelated donor was associated with poor overall survival (HR 3.7, 95 % CI 1.5-8.9 P value 0.004). In the absence of 1 antigen related or unrelated donor the use of 2nd allo-SCT was associated with better survival compared with boost only (i.e. no preparative regimen prior to cell infusion) (HR- 0.5, 95 % CI 0.3-0.9, p value 0.03)(Figure-1). Graft rejection/failure (39.7%) and infections (23.5%) were the commonest primary causes of death.Conclusions- GF post allo-SCT is a rare entity with sparse long term survivors despite interventions. For patients eligible to receive conditioning, use of RIC portends better engraftment and survival prior to cell rescue. [Display omitted] DisclosuresOran:Celgene: Research Funding; AROG: Research Funding; Astex: Research Funding. Khouri:Novartis: Research Funding.

Impact of Ruxolitinib in Myelofibrosis Allogeneic Stem Cell Transplant Outcome—a Pilot Study

Background: Myelofibrosis (MF) is a clonal stem cell disorder that develops de novo or evolves from a pre-existing myeloproliferative neoplasm such as polycythemia vera or essential thrombocythemia. MF is characterized by dysregulated proliferation of myeloid precursor cells and reactive deposition of connective tissue within the bone marrow, leading to bone marrow fibrosis and eventual failure from ineffective hematopoiesis. Common clinical manifestations include constitutional symptoms such as fatigue, fever, night sweats, weight loss, and hepatosplenomegaly. The clinical course and prognosis of MF is heterogenous, and survival outcomes are largely dependent on risk stratification that incorporates both phenotypic characteristics as well as cytogenetic features. Allogeneic stem cell transplant (alloSCT) is the only available treatment option to cure MF. Ruxolitinib (Rux), a potent JAK1/JAK2 inhibitor, has demonstrated significant effects in improving constitutional symptoms and reducing spleen size in intermediate to high risk patients. Hence, pre-transplant Rux treatment has often been practiced on patients with symptomatic splenomegaly and/or constitutional symptoms. Moreover, there are ongoing studies suggesting improved outcomes in patients treated with Rux before receiving alloSCT. However, the toxicity profile and tolerability profile of Rux treatment in transplant eligible patients remains unclear, especially the impacts of post-transplant Rux maintenance treatment.Method: We retrospectively analyzed the alloSCT outcomes among MF patients who never received Rux, received Rux before alloSCT, and received Rux before and after alloSCT at Penn State Hershey Cancer Institute between 6/2014 and 6/2017.Result: This pilot study analyzed 15 patients with mean age of 58.5 years old (range: 49-70) at the time receiving alloSCT. Ten patients were male and 5 patients were female. Those patients' MF scores were ranging from 2 to 3 (WHO Grade) at diagnosis. Five patients had primary MF and 10 had secondary MF. At diagnosis, all patients had constitutional symptoms, 14 of them had splenomegaly (1 had splenectomy before his MF diagnosis). Seven patients received Rux treatment before alloSCT, 4 received Rux before and after alloSCT, and 4 never received Rux. The mean length of time for Rux treatment before alloSCT was 8.3 months (range:5-20); the mean length of time for receiving Rux post alloSCT was 12.5 months (range:3-23). All patients received reduced intensity conditioning (RIC) regimen (14 patients received Fludarabine/Bu2, 1 patient received Fludarabine/Cyclophosphamide). One patient in the Fludarabine/Bu2 group also received total body irradiation (TBI) as part of conditioning regimen. The mean neutrophils engraft days for patients received Rux before alloSCT was 13.6 (range: 12-19), for patients received Rux before and after alloSCT was 13.3 (range: 12-16), and for patients never received Rux was 16 (range:13-18). All patients were transfusion independent at day 30 (D30) with >95% donor chimerism in peripheral blood. Following alloSCT, 4 patients restarted Rux at a mean time of 3.5 months (range: 3-4.5) post alloSCT. CMV viremia was detected in 5 patients before day 100 of alloSCT; in which 3 patients never received Rux. Fungal pneumonia (1 aspergillus) occurred in 3 patients who received Rux before allSCT. Multiple episodes of GVHD (grade II-III) occurred in 4 patients, however 3 of them never exposed to Rux before. One patient treated with Rux before alloSCT experienced liver GVHD (grade I to II) and responded well to steroids and immunosuppression treatment. The mean spleen size reduction in 6 months after alloSCT among patients received Rux before and after alloSCT was 26% (20 to 32%), among patients received Rux before alloSCT only was 18.2% (6 to 40%), and among patients never received Rux was 17.7% (12 to 24%). All patients are alive and in complete remission.Conclusion:Patients in this pilot study tolerated well to Rux treatment before and after alloSCT with neither prolonged engraft time nor increased toxicity. Before and after alloSCT Rux management may improve overall outcomes. Further study on large patient population is warranted. DisclosuresNo relevant conflicts of interest to declare.

ST2 As a Biomarker of Non-Relapse Mortality after HLA-Haploidentical SCT with High-Dose Post-Transplantation Cyclophosphamide

Intoduction:Allogenic hematopoietic stem cell transplantation (allo-SCT) is a curative procedure for several hematological malignancies. However, this treatment presents a significant morbidity and mortality, mainly related to infection, graft-versus-host disease (GVHD), and conditioning-related toxicity.In recent years, a number of tissue-specific proteins have been described as biomarkers that could contribute to anticipate post allo-SCT complications. ST2 (suppression of tumorigenicity 2)is a member of the interleukin-1 receptor family and It has been directly related to response to therapy of acute GVHD (aGVHD) and non-relapse mortality (NRM). Our objective was to analyze plasma levels of ST2 at days +15 and +30 post allo-SCT in patients who underwent unmanipulated haploidentical transplantation (HAPLO-HSCT), and to correlate with the NRM and GVHD.Material an methods:We retrospectively analyzed 110 consecutive patients (2009-2016) who underwent HAPLO-HSCT with post-transplant cyclophosfamide (days +3, +4), MMF and CsA as GVHD prophylaxis. A total of 23 cases were escluded, 9 cases due to early death (before day +30) and 14 cases due lack plasma sample. Characteristics of the 87 patients included in the analysis are described in Table 1. ST2 detection was performed by ELISA (Critical Diagnostics, San Diego, California) according to manufacturer's instructions on 200 μl of plasma obtained at day +15 and +30.The association of the incidence of aGVHD with known clinical variables and plasma ST2 levels were performed by Cox regression and Mann-Whitney U-test, respectively. The determination of the best cut-off of ST2 levels to stratified patients who died due to toxicity was performed with ROC curves. The statistical program used was R v2.15.0.Results:The cumulative incidence (CI) of grade II-IV and grade III-IV aGVHD at 100 days was 51.5% and 14.2%, respectively. CI of relapse and NRM at 2 years was 30% and 22.2% respectively.No association was found between usual clinical variables (stem cells source, age, sex, conditioning regimen intensity, disease status at trasplant, donor sex, and number of infused CD34 + cells) and NRM and with plasma ST2 levels at day +15 and +30. No differences were found between ST2 levels at day +15 and +30 and II-IV aGVHD, overal survival and steroid-resistant aGVHD.Highlight, plasma ST2 levels at day +30 were slightly higher in patients who devolped grade III-IV aGVHD compared to patients who did not (median and range, 2503 (524-5275) vs . 2146 (809-4572) ng/ml, p=0.12) with no stadistical significance.On the other hand, plasma ST2 levels at day +30 were significantly higher in patients with NRM compared to patients who did not (median and range, 2972 (1352-6072) vs. 2015 (809-5275) ng/ml, p= 0.022, Figure 1). Characteristics of NRM are shown in Table 2.The best cut-off selected on day +30 was 3230 ng/ml (E 82%, S 50%). Patients with higher levels than 3230 ng/ml at day +30 presented a significantly higher incidence of NRM (HR 10.4, p = 0.001, Figure 2).Conclusion:Plasma levels of ST2 at day +30 after HAPLO-HSCT correlated with the occurrence of NRM. Prospective studies are needed to better understand the kinetics of ST2 and its possible clinical application. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Determinants of Long-Term Survival Following Allogeneic Stem Cell Transplantation for Multiple Myeloma: A Multi-Centre Analysis Across the United Kingdom and Australia

IntroductionDespite the accepted utility of autologous stem cell transplantation for multiple myeloma, the role of allogeneic stem cell transplantation (alloSCT) remains controversial (Dhakal et al., 2016). The differences in practices across centres in patient selection, conditioning regimens and post-transplant care clouds the comparison of available studies. Moreover, the high rates of non-relapse mortality despite disease eradication demand an understanding of pre-allograft determinants of long-term survival. Included within these determinants is the appropriate timing for alloSCT, an important variable given the growing list of available myeloma therapies. We sought to identify the variables, including the influence of transplant centre and timing that govern long term survival following alloSCT for myeloma within integrated data in a large group of patients across three centres.MethodsA retrospective analysis of 93 patients undergoing alloSCT for multiple myeloma between January 2000 and June 2017 at three tertiary transplant centres - the Royal Melbourne Hospital, Australia and The Christie and Central Manchester NHS Foundation Trusts, United Kingdom. We collected: demographic data; disease-specific data, including previous treatment, disease status prior to alloSCT, and time from autologous SCT to alloSCT; and peri-transplant data including donor source and gender, stem cell dose, conditioning regime, and donor and recipient cytomegalovirus serological status. We measured overall survival, cause of death, acute and chronic graft versus host disease and progression free survival. Log-rank testing and cox regression analysis was performed with a multivariate regression model established on the basis of significant univariate associations.ResultsMedian age for the 93 patients at transplant was 49 years old (range 28 to 66 years). 65% of patients were male (n=60). 51 patients underwent alloSCT at the Royal Melbourne Hospital, 18 and 24 patients at the Christie and Central Manchester NHS Foundation Trusts, respectively. Patients received a median number of 2 lines of treatments prior to alloSCT (range 0-6). 51% (n=47) patients received stem cells from voluntary unrelated donors (VUD), and 49% from siblings (n=46). 78% (n=72) received a reduced intensity conditioning consisting of either 25mg/m2 fludarabine, 60mg/kg cyclophosphamide or 30mg/m2 fludarabine with 2Gy total body irradiation; 20% (n=18) received non-myeloablative conditioning with 30mg/m2 fludarabine and 750mg/m2 cyclophosphamide, 2% (n=3) underwent myeloablative conditioning with 60mg/kg cyclophosphamide and 4Gy total body irradiation.Median overall survival (OS) for the whole group was 8.1 years (interquartile range = 1.3 to 12.7 years). No difference was observed in OS across the three centres (log rank p=0.84) or across country (log-rank p=0.56). Conditioning regimens containing total body irradiation showed no association with relapse post allo SCT (odds ratio 0.68, 95% CI 0.30-1.55) and did not affect OS (hazard ratio, HR =1.00, 95% CI = 0.51-2.00).In accordance with previous findings (Dhakal et al., 2016), age over 40 at alloSCT was associated with a poorer survival (HR = 2.47, 95%CI 1.20 to 5.09). Patients who had stable or progressive disease at allograft showed poorer OS, even when controlling for number of lines of therapy and previous relapse (HR = 3.03, 95% CI 1.31-6.97).Patients who underwent alloSCT over one year following autologous SCT showed 3.4 times increased risk of death (95% CI 1.52-7.09) and 2.16 times increased risk of relapse (95% CI 1.18-3.93) even when controlling for age, prior relapse history, number of lines of treatment, disease status prior to alloSCT and transplanting hospital (Figure 1).ConclusionThis large multi-centre multivariate analysis demonstrates that transplant centre and low dose total body irradiation does not influence OS following alloSCT for multiple myeloma. Importantly, the time between autologous SCT and alloSCT of greater than one year is a strong predictor of poor OS. This remains true when controlling for several established risk factors. Our results demonstrate the importance of patient selection and timing in order to maximise OS for patients undergoing alloSCT for multiple myeloma.ReferenceDhakal B, et al. 2016. Allogeneic stem cell transplantation for multiple myeloma: is there a future? Bone Marrow Transplant, 51, 492-500. [Display omitted] DisclosuresRoutledge:Gilead: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Harrison:Celgene: Consultancy, Research Funding, Speakers Bureau. Cavet:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Speaker, Research Funding. Tholouli:Pfizer: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Ritchie:Amgen Inc.: Honoraria.

Early Maintenance with Tyrosine Kinase Inhibitors Post Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Improves Survival in Ph+ Acute Lymphoblastic Leukemia (ALL) Patients

Introduction: Addition of tyrosine Kinase inhibitors (TKI) to induction chemotherapy in management of Philadelphia chromosome positive (Ph+) ALL has significantly improved remission rates prior to allogeneic HSCT compared to the pre-TKI era. Consolidation with HSCT further prolongs remission and is potentially curative in the majority of patients. However, relapse is the commonest cause of treatment failure post HSCT with the highest incidence occurring within 18 months post-transplant. One possible strategy to minimize the risk of relapse is to commence TKI maintenance early post transplantation; which is increasingly becoming a common practice in many centers. However long term efficacy of this approach has not been established.Methods: A retrospective search for Ph+ ALL patients undergoing allogeneic HSCT from March 2001 to September 2015 (n=150) at our center was performed. From this cohort to determine the impact of prophylaxis we identified a subgroup of patients (n=99) who were in complete molecular response (CMR) before day +90 post HSCT. Subsequently we performed a day +90 landmark analysis to examine the outcome for patients according to whether or not they had commenced TKI maintenance by day +90 in a univariate and multivariate model. TKI maintenance was recommended but the final decision was based on feasibility and patient/physician preference.Results: Of the 99 patients included in the landmark analysis, 58.6% were men and 41.4% were women. Median age of study participants at the time of HSCT was 40 (range 3-64) years with a median follow up duration of 5.2 (range 1.1-15.0 ) years. At time of HSCT, 74.7% patients were in CR1, 16.2% were in CR2, and 9.1% were beyond CR2 or had primary induction failure. The majority of patients (97%) received a myeloablative preparative regimen, including radiation therapy in 31.3%. The median duration of TKI maintenance was 12.1 months (range 1-74 months). Imatinib was the commonest TKI used. Patients who received TKI maintenance (n=38) had superior 10-year probability of PFS and OS compared to patients who did not receive maintenance (n=61) at 68.1% vs 44.8%, p=0.005, and 67.1% vs 47.8%, p=0.004, respectively (Figure 1). TKI maintenance (HR=0.282, CI=0.122-0.654, p=0.001) and disease status pre-HSCT (beyond CR1) (HR=2.909, CI=1.286-6.577, p=0.01) were the two independent predictors for PFS in the multivariate model. Similarly, TKI maintenance (HR=0.244, CI=0.098-0.608, p=0.001) and disease status pre-HSCT (beyond CR1) (HR=3.394, CI=1.449-7.948, p=0.03) were the two independent predictor for OS. Both groups appeared to be well matched for several transplant/disease/treatment related variables.Conclusion: Prophylactic TKI maintenance early post allo-SCT is feasible and is associated with improved PFS and OS. Future prospective studies are needed to define the optimal duration of TKI maintenance to further improve outcomes for this historically adverse group. [Display omitted] DisclosuresOran:Celgene: Research Funding; AROG: Research Funding; Astex: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. Kantarjian:Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Delta-Fly Pharma: Research Funding.

This Is a Title in Chidamide, a Novel HDAC Inhibitor, Is Effective for Treating Leukemia Relapse Post Allogeneic Stem Cell Transplantation and Results in Th1 Polarization in AML Patients with AML1-ETO

Background: Although acute myeloid leukemia (AML) with t(8; 21) carries a favorable prognosis, relapse still occursin up to 40% of patients who require allogeneic stem cell transplantation (alloSCT). However, 10-20% of this patients suffer post-transplant relapse. AML1-ETO fusion protein can cause leukemogenesis via epigenetic modulation of AML1 target genes. In addition, emerging evidence support a role of this fusion protein in the downregulation of immune modulators on leukemia and subsequent immune evasion. Both process are histone deacetylase (HDAC)-dependent. Therefore we hypothesize that inhibition of HDAC may represent an effective treatment for AML with AML1-ETO. Chidamide is a novel HDAC inhibitor that has been CFDA approved for PTCL. In this study, we aim to test the safety and efficacy of Chidamide in post-transplant relapse AML with AML1-ETO.Method: This is a single arm, open label phase I study administrating Chidamide in AML patients with AML1-ETO who has molecular relapse post alloSCT. Chidamide is given 0.5mg/kg PO twice a week for children or 30mg PO twice a week for adults. All patients are treated for 3 months before analysis of molecular study. Treatment is continued for patients with persistently positive AML1-ETO, while discontinued in patients who achieved complete molecular remission (CMR). For patients not able to achieve CMR, DLI is added in addition to Chidamide. The primary objective is to determine the safety of Chidamide in AML post-transplant. The secondary objective is to evaluate overall response. Blood and bone marrow samples were collected prior to the treatment, monthly during the treatment, and 3 months after discontinuation of the treatment. Correlative studies for immune markers were performed by flow cytometry.Results: Seven patients have been enrolled in this study. No severe adverse event was observed. The most common adverse event was CTCAE grade 2 thrombocytopenia (7/7). Other adverse events that were possibly or probably related to Chidamide included grade 1 constitutional symptoms (7/7), reversible grade 2 transaminitis (3/7), grade 1 renal dysfunction (1/7), grade 1 digestive tract symptoms (4/7), grade 2 neutropenia (2/7), and grade 1 skin rash (4/7). No GVHD was observed in patients received Chidamide alone, whereas 2 patients received Chidamide and DLI developed grade 3 GVHD. Strikingly all 7 patients responded to Chidamide with decreased AML1-ETO level (ORR 100%). Among them, 6 patients achieved complete response (CR 85.7%), 1 patient had partial response (PR 14.3%) and eventually deteriorated.We also performed correlative studies and made several important findings. First, we assessed the distribution of each immune component from these 7 patients prior to Chidamide treatment, at which point all patients had molecular relapse. Samples from 4 patients who remain CMR post-transplant were used as controls. We observed a significantly decreased absolute counts of CD3+CD4-CD8+T cells in the patients with relapse, compared with that of patients remaining remission (272.0±63.7 vs. 2087.5±536.5, P=0.042), whereas NK cells, B cells, and CD3+CD4+CD8- T cells showed no statistical difference. Importantly there was a significant increase in percentages of Th2 and Th17 cells, while no difference of Th1 and FOXP3+Treg cells was observed. We next examined the level of Th1, Th2, and Th17 from the 7 relapse patients prior to treatment, compared with that from the same patient 1, 2, or 3 months post Chidamide treatment. We found that both percentages and absolute counts of Th1 cells increased gradually post treatment (26.0±12.8 vs. 190.8±43.4, P=0.027). In contrast, Th2 and Th17 cells decreased. Interestingly, at the time of 3 months after Chidamide discontinuation, the increased absolute counts of Th1 cells and decreased percentages of Th2 and Th17 remained. Furthermore, the Th1/Th2 ratio was low in patients with relapse disease. It increased gradually during Chidamide treatment, correlated with the down trend of AML1-ETO titer.Conclusion: Chidamide is safe and tolerable in AML patients with AML1-ETO who has post-transplant relapse. Although limited by sample size, our study showed promising clinical efficacy of Chidamide in AML. Importantly our study demonstrated a polarization for Th1 and the significant elevated ratio of Th1/Th2 in patients received Chidamide, which may contribute to the treatment efficacy of Chidamide for AML patients with AML1-ETO. DisclosuresWang:Meryx: Equity Ownership; University of North Carolina: Patents & Royalties.

Prospective PhaseⅡ Study of Reduced Toxicity Conditioning Consisted of High Dose-Cytarabine, Fludarabine, Cyclophosphamide +/- Total Body Irradiation Followed By Allogeneic Stem Cell Transplantation

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-SCT) using reduced intensity conditioning (RIC) has been widely applied to elderly or frail patients who are not eligible for conventional conditioning regimen. However, benefit provided by reduced toxicity has been often offset by increased incidence of relapse. So far, the optimal conditioning for those patients has not been established. Here, to investigate whether addition of high dose cytarabine (AraC) to RIC regimen consisting of fludarabine (Flu) and cyclophosphamide (Cy) +/- total body irradiation (TBI) can be available for elderly or frail recipients, phase II study has been designed.Methods: This study was conducted from April 2011 to December 2015. The protocol was approved by each institutional review board (Trial identifier: UMIN000007281). Patients aged from 55 to 70, or patients who have some organ damage or a history of SCT aged from 20 to 54 with hematologic malignancies were enrolled after obtaining written informed consent. Bone marrow (BM), peripheral blood (PB), or cord blood (CB) was used as stem cell sources. Pretransplant conditioning regimen consisted of 30 mg/m2 of Flu for 5 days (total 150 mg/m2), 4 g/m2 of AraC for 2-4 days (divided by 2 daily, total 8-16 g/m2) and 50mg/kg of Cy for a day. Four gray of TBI was used for all CB transplant recipients, whereas 2 gray of TBI was used in other stem cell sources except a matched related donor according to each institutional policy. Calcineurine inhibitors (cyclosporine or tacrolimus) and short term methotrexate were used as GVHD prophylaxis. Donor cell engraftment and 60 day-survival were assessed as a primary end point to evaluate feasibility of this protocol.Results: Thirty nine patients including 7 recipients with a history of SCT were enrolled. Median age was 61 (28-69), 21 were male, and 18 were female. Nineteen were acute myeloid leukemia, 11 myelodysplastic syndrome, 6 malignant lymphoma and 3 acute lymphoblastic leukemia. Donors were 4 matched related PB, 8 matched unrelated BM, 5 1-Ag/allele-mismatched unrelated BM, and 22 ≤2-Ag-mismatched CB. Thirty seven (94.9%) patients have passed 60-day-point post-transplant. In 38 (97.4%) recipients, engraftment was obtained, a patient died before engraftment due to sepsis caused by enterococcus faecium (male CB recipient, 55y, day15). Median neutrophil recovery to over 500/μl was obtained on day 19 (16-38). Fourteen blood stream infections (13 bacteremias and 1 candidemia) judged as grade 3 toxicity and 2 cases (1 sepsis and 1 endotoxemia ) of grade 4 toxicity were observed within 60 days post-transplant. There were 2 deaths of post-engraftment due to cerebral bleeding (1 female CB recipient, 64y, day 46) and GVHD (1 male CB recipient, 60y, day 77) within 100 days. Although no relapse was observed up to day 60, 7 relapses were observed up to 1 year. Overall survival and disease-free survival were estimated to be 82.1% and 73.8 % at 1 year post-transplant, respectively.Conclusions: RIC using Flu/high dose AraC /Cy +/- TBI was well tolerated with acceptable low toxicities and was sufficient to allow donor cell-engraftment post allo-SCT for elderly or frail patients with hematologic malignancies. Longer follow up and another prospective study enrolling more patients are required to evaluate the eventual survival benefit by reducing relapse. DisclosuresNo relevant conflicts of interest to declare.

Combined Azacitidine and High Dose Lenalidomide Therapy Is Well Tolerated and Clinically Active in Patients Who Relapse after Allogeneic Stem Cell Transplantation for Actue Myeloid Leukemia: Results of the Uk Trials Acceleration Programme Viola Trial

▪Introduction: The outcome for patients who relapse after allogeneic stem cell transplantation (allo-SCT) remains extremely poor and the development of novel salvage regimens represents a major unmet clinical need. Intensive chemotherapy is not only frequently ineffective in this population but also associated with substantial toxicity which substantially limits its utilization in practice. Both azacitidine (AZA) and lenalidomide (LEN) represent promising salvage agents post allograft not only because they demonstrate significant anti-tumor activity as monotherapy in AML and MDS but also because they have the potential to augment the graft-versus-leukemia effect. AZA is well tolerated post-transplant and results in a reduced risk of graft-versus-host disease (GVHD) in animal models but is associated with only modest clinical activity in patients who relapse after allo-SCT. LEN, however, results in excessive rates of severe GVHD when administered post-transplant which has limited its assessment as a salvage therapy in this setting. Reasoning that AZA may reduce the GVHD risk associated with LEN administration we evaluated the safety and efficacy of combined LEN and AZA therapy in patients with relapsed AML post allo-SCT. Patients and Methods: 29 patients with morphological evidence of disease relapse at a median of 10 months after allo-SCT were treated with escalating doses of LEN (0 mg, 2.5mg, 5 mg, 10 mg, 15 mg, 25 mg, 35 mg) in combination with AZA (75 mg/m2) x 7 days in 28 day cycles. 24 patients were transplanted for AML and 5 for MDS using a matched sibling (n = 13) or unrelated donor (n=16). Patients received a median of 3 cycles of LEN/AZA combination therapy.The maximum tolerated dose (MTD) of LEN/AZA combination therapy was estimated using a modified continual reassessment method (CRM) based on occurrence of dose-limiting toxicities observed within the first cycle. Clinical response was assessed after every 3rd cycle using modified Cheson criteria. The frequency of CD3+ T cells and their expression of PD1, LAG3, and TIM3 exhaustion markers was analyzed in all samples by flow cytometry. T cell activation status was determined by PMA and ionomycin stimulation followed by cytokine profile analyzing bead-array flow cytometry. Results: Using an efficient CRM model a dose of 25 mg LEN (days 10-30) in combination with AZA 75 mg/m2 x 7 days (days 1-5, 8-9) was established as the MTD. Only one patient developed Grade 3-4 GVHD during LEN/AZA combined therapy. Major clinical responses were observed in 7 of the 15 patients who received three or more cycles of combined LEN/AZA treatment: CR/CRi n=6, PR n=1. Acquisition of a major clinical response was associated with prolonged overall survival (OS): median OS 17.3 versus 3.2 months (p<0.001). Increased levels of PD1 and LAG3 expression were present on CD3+ T cells at baseline compared with healthy controls (p=0.0025 and p=0.0177 respectively) consistent with a T cell exhaustion phenotype. T cells demonstrated impaired IFN-γ/TNF-α production at relapse and this was not reversed during LEN/AZA therapy. Conclusion: High doses of LEN can be safely delivered post-allograft when co-administered with AZA. Assessment of the MTD in this very high risk patient population was accelerated by the adoption of a CRM design which coped effectively with the challenges of cohort variation and early patient drop out. LEN/AZA combination therapy demonstrates promising clinical activity supporting further prospective evaluation as a novel salvage strategy post-transplant. Preliminary data supports combined LEN/AZA therapy exerting an anti-leukemia effect through a PD1 independent pathway. DisclosuresCavenagh:Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Christina:Celgene: Honoraria.

Personalized Circulating Tumor DNA Predicts Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome

Background: Relapse is a main event of therapy failure for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) undergoing allogeneic hematopoietic stem cell transplantation (alloSCT). Hence, a novel strategy to detect minimal residual disease (MRD) is required for earlier therapeutic intervention in impending post alloSCT relapse. Recent evidence indicated that screening of driver mutations by next generation sequencing (NGS) followed by detection of circulating tumor DNA (ctDNA) via droplet digital PCR (ddPCR) is a promising approach for MRD monitoring in patients with MDS (Paul Y, et al. Blood. 2017). Here, in this study, we investigated whether serial ctDNA monitoring could identify patients who are most likely to relapse after alloSCT.Methods: We performed a retrospective study in 31 patients with AML and MDS undergoing alloSCT. Cell-free DNA (cfDNA) was extracted from serum samples. We subjected primary tumor DNA, extracted from a diagnostic peripheral blood or bone marrow (BM), and buccal swab DNA, to NGS, identifying one or two somatic driver mutations. We designed unique ddPCR assays for each somatic mutation identified (n=25). The primary endpoint was cumulative incidence of relapse rate (CIR) and the secondary endpoint was overall survival (OS). CIR and OS were calculated by the Kaplan-Meier method. The log-rank test was used for group comparison.Results: 31 patients were enrolled in our study: our cohort consisted of 10 patients with de novo AML, 15 with AML with myelodysplasia related changes, and 6 with MDS. The median age was 52 years (17-68 years) and 5 patients (16%) are in complete remission at alloSCT. Stem cell source included related bone marrow (n=2) and cord blood (n=29). The preparative regimen included myeloablative conditioning (n=17) and reduced intensity conditioning (n=14). NGS screening identified 26 somatic driver mutations in 30 of 31 (97%) cases, with 2 mutations found in 5 individuals. Overall, we could construct ddPCR assays for 29 of 31 (94%) patients: these mutations included NRAS, TP53, NPM1, DNMT3A, GATA2, etc. NGS and ddPCR assays had a good concordance in assessing the same tumor rich samples with regard to the variant allele frequency (VAF).The amount of cfDNA at diagnosis was significantly higher compared with paired cfDNA at remission (n=23; p=0.0133, paired t-test). Of 37 matched serial time points, VAF between BM and serum ctDNA indicates apparent correlation (r2=0.92, p<0.0001). CtDNA was detected in 10 of 25 (40%) samples at 1 month after alloSCT and 7 of 21 (33%) samples at 3 months (termed “ctDNA1-positive” and “ctDNA3-positive”, respectively).We next evaluated whether the positivity of ctDNA at 1 month and 3 months after alloSCT was associated with higher CIR and lower OS. As expected, patients with ctDNA1-positive and ctDNA3-positive had significantly superior CIR and inferior OS: 2-year CIR 51% in ctDNA1-positive patients vs. 9% in negative patients, p=0.0005 (Figure 1A); 2-year OS 48% in ctDNA1-positive patients vs. 83% in negative patients, p=0.0152 (Figure 1B); 2-year CIR 57% in ctDNA3-positive patients vs. 23% in negative patients, p=0.0055 (Figure 1C); 2-year OS 50% in ctDNA3-positive patients vs. 88% in negative patients, p=0.0344 (Figure 1D), respectively.Conclusions: In summary, personalized ctDNA monitoring could detect MRD, which alloSCT has failed to eradicate, and thus identify patients with high-risk of relapse. This might allow for clinicians to initiating earlier therapeutic interventions for impending relapse. Further prospective studies in a much larger cohort of AML and MDS undergoing alloSCT are required to confirm these findings.Figure 1. CIR and OS based on ctDNA status at 1 month and 3 months after alloSCT [Display omitted] DisclosuresNagamura-Inoue:Tsubakimoto Chain CO.: Research Funding; AMED grant: Research Funding; Rohto Pharmaceutical Co., Ltd.: Research Funding. Tojo:AMED grant: Research Funding.