ALBERT

Description: Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia-causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps to the commonly deleted 7q region. We demonstrate that DOCK4 is underexpressed in MDS bone marrow samples and that the reduced expression is associated with decreased overall survival in patients. We show that depletion of DOCK4 levels leads to erythroid cells with dysplastic morphology both in vivo and in vitro. We established a novel single-cell assay to quantify disrupted F-actin filament network in erythroblasts and demonstrate that reduced expression of DOCK4 leads to disruption of the actin filaments, resulting in erythroid dysplasia that phenocopies the red blood cell (RBC) defects seen in samples from MDS patients. Reexpression of DOCK4 in −7q MDS patient erythroblasts resulted in significant erythropoietic improvements. Mechanisms underlying F-actin disruption revealed that DOCK4 knockdown reduces ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase activation, leading to increased phosphorylation of the actin-stabilizing protein ADDUCIN in MDS samples. These data identify DOCK4 as a putative 7q gene whose reduced expression can lead to erythroid dysplasia.

Description: The optimal source of donor hematopoietic stem cells (HSC) is controversial. Granulocyte colony stimulating factor (G-CSF) mobilized peripheral blood (G-PB) has replaced bone marrow (BM) as the most common allograft source in adults but is associated with donor morbidity and higher rates of chronic graft versus host disease (GVHD) compared to BM. The CXCR4 antagonist plerixafor (Px) mobilizes HSC into the PB (Px-PB) faster than G-CSF and preliminary data suggest both quantitative and qualitative differences in allograft content that may impact clinical outcomes. We sought to assess the efficacy and safety of transplanted allografts collected following mobilization with Px alone in HLA-identical sibling transplantation. This was a Phase II, two-strata, multi-center prospective trial (NCT01696461) to evaluate Px-PB allografts prior to reduced intensity conditioning (RIC) and myeloablative conditioning (MAC) based hematopoietic cell transplantation (HCT). Patients aged 18-65 years with an HLA-ID sibling donor and a hematological malignancy suitable for HCT were eligible. The primary objective was to determine the proportion of donors whose cells could be successfully mobilized and collected with a sufficient CD34+ cell dose using Px as the sole mobilizing agent. Px mobilization was considered successful if ≥ 2.0x10^6 CD34+ cells/kg recipient weight were collected in no more than two leukapheresis (LP) collections. All donors receiving Px were included in the analysis of the primary objective based on the intention-to-treat principle. Secondary objectives included the incidence of acute and chronic adverse events in donors, rates of hematopoietic engraftment, donor chimerism, rates of acute and chronic GVHD, non-relapse mortality (NRM), progression free survival (PFS) and overall survival (OS) for the recipients. From July 2013 to December 2014, 64 donor/recipient pairs were enrolled at 12 centers. Donors received Px at 240μg/kg subcutaneously 4 hours prior to LP. LP was performed processing at least 4X blood volume for up to two consecutive days (a third day was allowed for low CD34+ cell yields after 2 LP procedures) to achieve a target CD34+ cell dose of ≥ 4.0 x 10^6/kg recipient weight with a minimum goal of ≥ 2.0 x 10^6/kg. All allografts were cryopreserved. GVHD prophylaxis included cyclosporine or tacrolimus in combination with methotrexate, mycophenolate mofetil, or sirolimus. G-CSF was given routinely post HCT only to MAC recipients. Patient demographics are provided in Table 1. The median donor age was 56 years (18-65). 64% of the donors were male. Donors underwent one (23%), two (72%), or three (5%) LP procedures. 63 of 64 (98%) donors achieved the primary objective. The median total CD34+ cell dose/kg recipient weight collected within 2 days was 4.6 (0.9-9.6). Maximal donor toxicity following Px injection and LP was grades 0 (30%), 1 (52%), 2 (17%), and 3 (2%). Bloating, flatulence, abdominal pain, headache, paresthesisas, injection site reaction, and dizziness were the most commonly observed toxicities. Bone pain was not observed. The one grade 3 toxicity was a vasovagal episode felt related to LP and unlikely to Px. Toxicities typically resolved within a week of LP. The median follow up is 6.3 months. Median days to ANC (〉0.5 x10^9/L) and Platelet count (〉20 x 10^9/L) recovery were 13.5 (10-148) and 19 (1-76) after MAC and 14.5 (0-25) and 18 (0-141) after RIC, respectively. The cumulative incidence of acute GVHD grades 2-4 and 3-4 at day 100 were 47% (95% CI: 30-64) and 9% (95% CI: 2-22) after MAC and 19% (95% CI: 6-38) and 5% (95% CI: 0-18) after RIC. Probability of NRM at day 100 was 4% (95% CI: 0-13) and 0% after MAC and RIC, respectively. The probability of OS at day 100 was 97% (95% CI: 88-100) and 90% (95% CI: 78-98) after MAC and RIC, respectively. In conclusion, this is the first multi-center trial to demonstrate that as an alternative to G-CSF, Plerixafor rapidly, safely, and effectively mobilizes sufficient numbers of CD34+ cells from HLA-ID sibling donors for HCT following both RIC and MAC regimens. Engraftment was generally prompt and early results of secondary endpoints in recipients are encouraging. Longer follow-up and more extensive analysis of donor allografts and recipient outcomes will be presented at the time of the meeting. Research support was provided in part by Genzyme, a Sanofi Company. Table 1. Characteristics of recipients Table 1. Characteristics of recipients Disclosures Chen: Bayer: Consultancy, Research Funding. Devine:Genzyme: Research Funding.

Description: Background: Treatment with rhu-Epo ameliorates anemia in a subset of LR-MDS patients, however, effective salvage therapy is limited. LEN promotes erythroid lineage competence and expansion of primitive erythroid precursors in vitro. In the MDS-002 and MDS-005 trials, treatment with LEN improved erythropoiesis, yielding RBC transfusion-independence in 26% of azanucleoside-naïve, transfusion-dependent (TD) LR, non-del(5q) MDS patients for a median of 10.2 and 7.75 months, respectively. We previously reported that LEN restores Epo-responsiveness in MDS progenitors by inducing formation of lipid rafts enriched for signaling competent JAK2/Epo-receptor complexes and excluding large isoforms of the JAK2/lyn kinase-phosphatase CD45 (McGraw K, et. al. PLoS One 2014; Basiorka A, et. al. Cancer Res 2016). In a pilot study of Epo-refractory MDS patients, addition of EA yielded erythroid responses in 28% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome resistance and augment response to rhEpo (Komrokji R, et. al. Blood 2012). To test this hypothesis, we performed a randomized phase III trial comparing treatment with LEN to LEN+EA in LR non-del(5q) MDS patients who were refractory to, or not candidates for treatment with rhEpo. Methods: Patients with Low or Intermediate-1 (Int-1) risk IPSS MDS with hemoglobin 2 units/mo) with serum Epo 〉500mU/mL were eligible for study. Patients were stratified by serum Epo level and prior rhEpo (EA vs. darbepoetin vs. none) then randomized to treatment with LEN 10 mg/d x21d q4wk (Arm A) or LEN + EA 60,000U SC/wk (Arm B). Primary endpoint was IWG 2006 major erythroid response (MER) rate after 4 cycles. Arm A non-responders were offered cross-over to combined therapy. Secondary endpoints included analysis of response biomarkers. Results: Between April 2009 and May 2016, 248 patients were enrolled and 195 were randomized and will be included in the primary analysis. Interim analysis of 163 patients (Arm A, 81; B, 82) accrued before July 2015 showed that the study met predefined stopping criteria. Baseline characteristics were balanced between arms. Median age was 74 years (range, 47-89) receiving a median of 2 RBC units/mo (0-8). Overall, 64 (39%) patients had Low IPSS risk and 90 (55%) Int-1 risk. Among these, 150 received prior rhuEpo (92%) and 27, azanucleosides (17%). In an ITT analysis, MER rate was significantly higher with combination therapy, Arm B 25.6% (n=21) vs. Arm A 9.9% (n=8) (P=0.015). Among 116 patients evaluable at week 16, 33.3% (20/60) and 14.3% (8/56) achieved MER, respectively (P=0.018), with a median response duration of 25.4 months vs. not reached in Arm A responders. Response to combined treatment was associated with baseline CD45-isoform distribution in erythroid precursors. Patients achieving MER had a significantly lower CD45 RA+RB:RO ratio (median, 1.51) compared to non-responders (median, 4.21; P=0.04), favoring homo-dimerization of the short CD45-RO isoform and inhibition of phosphatase activity. MER rate in Arm B patients with a low isoform ratio (〈 median) was 72.7% vs. 18.2% in the high ratio group (P=0.03). Thirty-four Arm A non-responders crossed over to combination-therapy with only 1 MER. There was no difference in the frequency or distribution of 〉Grade 3, non-hematologic AEs. Conclusions: LEN restores sensitivity to rhEpo in Epo-refractory LR-non-del(5q) MDS patients to yield durable and significantly higher rates of erythroid response to combination treatment without added toxicity. Erythroid CD45 isoform profile may serve as a response biomarker for selection of candidates for combination therapy. Disclosures Bennett: Celgne: Membership on an entity's Board of Directors or advisory committees. Altman:Syros: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Schiffer:Teva: Other: DSMB member; BMS: Research Funding; Ariad: Research Funding; Pfizer: Other: DSMB member.

Description: LK, SS Equal contributions VG, JTP Equal credit as senior authors Prolyl hydroxylase 2 (encoded by EGLN1), the principle negative regulator of HIF-1 and HIF-2 (encoded by EPAS1), is an iron dependent enzyme (Kaelin WG et al. Mol Cell, 2008); thus iron deficiency can augment hypoxic responses (Zhang X et al Blood Cells Mol Dis, 2014). Because EPAS1 mRNA has a 5' iron regulatory element, iron deficiency may inhibit the translation of HIF-2α and downregulate its target genes (Sanchez M et al Nat Struct Mol Biol, 2007). The Partnership for Anemia: Clinical and Translational Trials in the Elderly conducted a trial to determine the efficacy of IV iron in patients with borderline iron deficiency (Price E et al. Blood Cells Mol Dis, 2014). We measured expression levels of HIF1A, EPAS1, EGLN1 and HIF target genes in platelets and granulocytes. Nineteen patients were treated with 200 mg IV iron sucrose weekly for 5 weeks. Blood was obtained at screening, one week after the second dose of IV iron and 8 weeks after completion of iron therapy. Granulocytes and platelets were isolated and their RNA reverse transcribed. Transcripts were quantified by real-time qT-PCR, and normalized to HPRT gene. The threshold cycle for the expression of each gene was calculated and compared to 5 healthy controls. We found a positive correlation between granulocyte and platelet mRNA of HIF1A, EPAS1 and EGLN1, and these relationships achieved a one-sided significance level of 0.1 or stronger for most data points for HIF1A and EPAS1 (Table 1). There was also a positive correlation for granulocyte and platelet mRNA of 5 of 7 hypoxia response genes (P of 0.1 or stronger in many comparisons; the strongest being for VEGF and PDK1). Table 1. Spearman correlation rho between granulocyte and platelet mRNAs (N = 17). Gene Screen TV2 FU2 Regulators of the hypoxic response HIF1A .52** .21 .40* EPAS1 .40* .54** .67** EGLN1 .28 .30 .09 Responders to the hypoxic response GLUT1 .44** .00 .07 HK1 .25 .20 .36* PDK1 .24 .55** .41* VEGF .68** .33* .62** FOXO3 -.10 .22 .45** BNIP3 .03 -.19 -.08 BNIP3L .15 -.05 .20 *one-sided P

Description: Background: Only a small subset of Lower risk (LR) MDS patients benefit from treatment with rhu-Erythropoietin (Epo). We previously reported that lenalidomide (LEN) restores sensitivity to Epo in MDS progenitors by inducing the formation of lipid rafts that are enriched for signaling competent, JAK2/Epo-receptor complexes (McGraw K, et. al. PLoS One 2014; Basiorka A, et. al. Cancer Res 2016). In the MDS-002 and MDS-005 trials, treatment with LEN monotherapy gave rise to RBC transfusion-independence (TI) in 26% of azanucleoside-naïve, transfusion-dependent (TD) LR, non-del(5q) MDS patients for a median of 10.2 and 7.75 months, respectively. In a pilot study of Epo-refractory LR-MDS patients, the addition of epoetin alfa (EA) to LEN treatment yielded erythroid responses in 28% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome clinical resistance to augment response to rhEpo (Komrokji R, et. al. Blood 2012). To test this hypothesis, we performed a randomized phase III trial comparing treatment with LEN to LEN+EA in LR non-del(5q) MDS patients who were refractory to, or not candidates for treatment with rhEpo. Methods: Patients with Low or Intermediate-1 IPSS risk MDS with hemoglobin 2 units/month) with serum Epo 〉500mU/mL were eligible. Patients were stratified by serum Epo level and prior rhEpo (EA vs. darbepoetin vs. none) then randomized to treatment with LEN 10 mg/d x21d q4wk (Arm A) or LEN + EA 60,000U SC/wk (Arm B). The primary endpoint was major erythroid response (MER) at week 16 which was defined according to transfusion status at baseline: (1) achievement of RBC-TI for ≥ 8 consecutive weeks AND a sustained ≥1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value in TD patients; and (2) a 〉2 g/dL rise in hemoglobin without transfusion for ≥ 8 consecutive weeks in non-TD patients (Grade 3, non-hematologic adverse events between treatment arms. Two patients progressed to AML while on study (Arm A), and no thromboembolic events were reported. Conclusions: LEN restores sensitivity to rhEpo in otherwise refractory, LR-non-del(5q) MDS patients to yield a significantly higher frequency of durable major erythroid responses compared to LEN alone. The addition of LEN to EA treatment is an effective strategy for the management of Epo-refractory patients with a potential duration of benefit extending to years. Disclosures List: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Verma:Janssen: Research Funding; BMS: Research Funding; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria. Maciejewski:Novartis: Consultancy; Alexion: Consultancy. Komrokji:JAZZ: Speakers Bureau; Novartis: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; celgene: Consultancy; pfizer: Consultancy. Luger:Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding; Cyslacel: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria; Genetech: Research Funding; Jazz: Honoraria; Daichi Sankyo: Honoraria; Kura: Research Funding; Celgene: Research Funding. Mattison:Pfizer: Membership on an entity's Board of Directors or advisory committees. Altman:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; France Foundation: Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Cancer Expert Now: Consultancy; Novartis: Consultancy; Biosight: Other: US Lead. Claxton:Astellas Pharma: Other: Pharma support of clinical studies; Merck Sharp & Dohme Corp.: Other: Pharma support of clinical studies; Cyclacel Pharmaceuticals, Inc.: Other: Pharma support of clinical studies; Medimmune Inc.: Other: Pharma support of clinical studies; Novartis Pharmaceuticals: Other: Pharma support of clinical studies; Celgene Corporation: Other: Pharma support of clinical studies; Incyte Corporation: Other: Cyclacel Pharmaceuticals, Inc; Daiichi Sankyo Co. and Ambit Biosciences Corp: Other: Pharma support of clinical studies. Artz:Miltenyi: Research Funding. Tallman:Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Lenalidomide used for treatment non-del 5q myelodysplastic syndromes.

Description: Introduction: Filgrastim is widely used for mobilizing CD34+ cells into the peripheral blood that are easily collected by apheresis for allogeneic transplantation. With case reports documenting splenomegaly with life-threatening complications in normal donors, we prospectively evaluated spleen size using ultrasonography and clinical examination during PBPC mobilization and collection in a single-arm trial. Methods: Subjects ≥18 yrs eligible to be PBPC donors per institutional guidelines enrolled. Splenic assessments were done before, during, and after PBPC mobilization. Filgrastim dose and schedule and leukapheresis (LK) procedures were per institutional practice. The primary endpoint was fold change from baseline in splenic volume in post-baseline measurements during mobilization (measured by ultrasound [US]). Spleen size by US was measured in 3 dimensions similarly by all centers: longitudinal (craniocaudal), transverse, and diagonal (perpendicular to transverse in transverse image) diameters. Splenic volume was estimated by taking the cross-product of 3 dimensions and multiplying by 0.52, approximating the volume of an ellipse. Physical examination was performed on US days, assessing spleen palpability. US and palpation results were blinded from each other at assessment times. Timepoints included baseline (before first filgrastim dose), first LK (done before LK, typically day 4 or 5 of filgrastim), 2 and 4 days after first LK, and 7 days after last LK. Timepoints in the post-amendment cohort (n=219) were reduced to facilitate enrollment and were baseline and day of first LK (before LK). Results: 309 donors enrolled, median age 44yrs (range 18 to 74), 56% male. Mean daily filgrastim dose was 11.4mcg/kg (SD=3.0). Median number of LK was 1.5 (range 1 to 4). In all donors, the median increase in each measured dimension on first LK day was 1.4cm, 1.4cm, and 0.6cm (12.8%, 12.6%, and 15.0%), and the median fold volume increase from baseline to first LK was 1.47, resolving to near baseline 1 week after last LK. There was no apparent relationship between volume fold change and filgrastim dose, ANC, or CD34+ yield. Of 861 splenic palpation assessments reported in all donors, 98% were reported as nonpalpable (842 assessments), and 2% were palpable (19 assessments, 2 at baseline). Reporting of palpable spleens did not correlate with increased spleen size. Tenderness or guarding upon splenic palpation was reported in 2 donors with a spleen considered palpable and in 6 donors with nonpalpable spleens. No donor experienced a splenic rupture. Adverse events related to filgrastim were generally mild to moderate. Conclusion: During PBPC mobilization with filgrastim in normal donors, the spleen increased a median of approximately 50% from baseline to day of first LK and returned to near baseline 1 week after last LK. Size change was not associated with significant clinical sequelae. Timepoint Median fold change from baseline in splenic volume (Q1, Q3) *statistically significant (p

Description: Rationale: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the most effective therapy for patients with acute myeloid leukemia (AML). The graft-versus-leukemia effect (GVL), mediated by the engrafted T lymphocytes targeting leukemic cells, is thought to play an important role in affecting the overall outcome of patients with AML. Umbilical cord blood (UCB) has emerged as an alternative and effective source of hematopoietic stem cells in high risk patients. We previously reported the hematopoietic reconstitution and clinical outcomes in 45 patients undergoing haplo-cord transplant, a novel approach which combines haploidentical and cord blood grafts to avoid delayed hematopoietic recovery after cord blood transplant (Liu H,et al. Blood. 2011;118(24):6438-45). However, very little is known about immune reconstitution of cord blood cells and whether the emerging immune repertoire correlates with clinical outcome. The great majority of T cell receptors in T lymphocytes are heterodimers of alpha (TCRA) and beta (TCRB) subunits. Somatic recombination combining the VJ (alpha) and VDJ (beta) segments results in an astronomical functional diversity and complexity of TCR receptors, and makes the characterization of their functions a tremendously complex process. To obtain insights into the T-cell repertoire, we have utilized next-generation sequencing (NGS) technology to comprehensively characterize T-cell kinetics and diversity following haplo-cord transplantation. Methods: We evaluated the emerging T-cell repertoire in 10 patients (pts) with high-risk AML enrolled on a clinical trial of haplo-cord transplantation at the University of Chicago. The median age of the pts was 57 years old (range: 26-67) and 3 pts had active disease at the time of transplant. The median UCB dose was 1.6x107 TNC/kg with HLA cord matching of 4/6 in 3 pts and 5/6 or 6/6 in 7 pts. The median overall and disease free survival were 2.4 and 2.2 years, respectively. cDNA was generated from mRNA isolated from peripheral blood mononuclear cells prior to and at sequential time points 30, 100, 180 and 365 days post haplo-cord transplant were sequenced the samples with Ion Personal Genome Machine (PGM) Sequencer and a 400-bp reading kit. We analyzed the sequences by applying a recently developed algorithm in order to determine the VJ and VDJ combinations and CDR3 sequences. Chimerism was determined by microsatellite sequences of DNA of donor and recipient cells. Diversity was calculated for each of TCRA and TCRB using the inverse Simpson’s index. Results: Several clones found in pre-treatment samples obtained from recipients before transplant persisted at low frequency on days 100 and 365 post-transplant suggesting that these clones have evaded the immuno-suppressive conditioning regimens. In order to correlate the diversity of TCRs with the percentage of cord cells in patients’ blood at different time points, we dichotomized patients into cord present (〉5%) and cord absent (≤5%) groups, based on the cord blood percentage in blood on day 30 post haplo-cord transplant and correlated it with diversity on day 100. We found that TCRs of pts with 〉5% cord cells on day 30 post haplo-cord transplant were significantly more diverse (TCRA; P=0.008) and (TCRB; P=0.01) (Fig.1) on day 100 compared to TCRs in patients with 90% cord cells on day 100 post-transplant. Therefore, we examined the correlation between diversity calculated on day 100 and percentage of persisting haplo-identical cells on the same day. We found,, the diversity of TCRB of pts with persistence of 〉10% haplo-identical cells were 15.05 compared with 72.95 for those with 10% and

Description: Background: Disease relapse remains the primary cause of mortality following allogeneic hematopoietic cell transplantation (alloHCT). One important mechanism of disease relapse in this setting is failure of the graft-versus-tumor (GvT) effect, and the PD-1/PD-L1 axis may diminish GvT after alloSCT. We hypothesized that PD-1/PD-L1 interactions prevent donor-derived T cells from eliminating malignant cells expressing minor histocompatibility antigens, and that blocking PD-1/PD-L1 interactions with the anti-PD-1 antibody, pembrolizumab (pem), might restore GvT and induce clinical responses in patients (pts) with relapsed hematologic malignancies following alloHCT. However, PD-1 blockade therapy has been associated with severe graft-versus-host disease (GVHD) in murine models, and GVHD has been reported in humans treated with anti-PD-1 therapy after alloHCT. Thus, we developed a prospective clinical study to test the tolerability and preliminary efficacy of pembrolizumab in patients with relapsed leukemia/lymphoma after alloSCT. Methods: Pts with AML, MDS, or B cell lymphomas with biopsy-proven recurrence after alloSCT were eligible, as long as no active acute GVHD 〉 grade 1 or chronic GVHD was present. Pts were treated with pem 200 mg IV q3 weeks for up to 2 years, provided that neither intolerable side-effects nor disease progression occurred. Pem could be delayed for treatment-limiting toxicities (TLT), defined as immune-related adverse events (irAEs) not meeting criteria for a dose-limiting toxicity (DLT). DLT was defined as the development of grade 3 or 4 acute GVHD/irAE, any unexpected grade 〉 2 toxicity related to pem, or development of 〉 grade 2 vital organ dysfunction secondary to an irAE within 90 days of pem initiation. A two-stage mini-max design was chosen, with an early stopping rule for DLT after the first 11 patients were enrolled. Results: 11 pts (7 male, 4 female), mean age 49.5 yrs (range, 27-62 yrs) have been enrolled. 8 pts had AML and 3 had lymphoma (DLBCL - 2, cHL - 1). 6 pts had matched-related donors (MRD) and 5 pts had haploidentical/umbilical cord blood (haplo-cord) donors. Pts with MRD were conditioned with fludarabine, melphalan, and alemtuzumab, or fludarabine and busulfan. Pts with haplo-cord donors were conditioned with fludarabine, melphalan, and ATG. 5 pts had prior acute GVHD. Pts relapsed following alloHCT at a median of 453 days (range, 101-1021 days). A median of 2 cycles of pembrolizumab (range, 1-8) was administered. 3 pts are receiving ongoing treatment. 3 pts experienced a DLT due to an irAE (grade 3-4 pneumonitis 2 pts; grade 3 hyperthyroidism 1 pt), all of which occurred after 1-2 cycles of pem, and resolved after pem discontinuation and corticosteroid treatment. 1 pt experienced a TLT (grade 2 rash), but resumed pem treatment. Among all pts, irAEs of any grade occurred in 7 pts. 7 pts were evaluable for response. 3 pts (2 AML, 1 DLBCL) experienced progressive disease (PD), 2 pts (AML) had stable disease (SD), and 2 pts achieved CR (DLBCL, cHL). 1 pt with AML (myeloid sarcoma) in whom pem was discontinued for PD by PET/CT imaging had a concurrent tumor biopsy that revealed marked T cell infiltration and PD-L1 expression on a significant fraction of malignant myeloid cells, suggestive of possible inflammatory "pseudo-progression". 1 pt in CR developed therapy-related AML unrelated to pem. Notably, both patients with CR following pem had PD-L1 gene-amplified lymphomas by FISH, and diffuse PD-L1 protein expression on pre-treatment biopsies. Currently, 4 pts have died, all due to disease progression, and 7 are alive. A total of 26 patients are expected to be enrolled. Conclusions: Treatment with pem in the post-alloHCT disease relapse setting is feasible, but can induce early and severe irAEs, requiring vigilant monitoring. To date, objective responses were seen in 2/3 lymphoma patients treated with pem. In AML, pem may be less effective, where a best response of SD was observed in 2 pts, and possible "pseudo-progression" in a patient with myeloid sarcoma. This study continues to accrue pts, and correlative analyses are underway. To our knowledge, these are the first prospective data of PD-1 blockade therapy in the post-alloHCT setting. Disclosures Kline: iTeos: Research Funding; Merck: Honoraria, Research Funding. Liu:BMS: Research Funding. Curran:Merck: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Bishop:Juneau Therapeutics: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; United Healthcare: Employment; Novartis Pharmaceuticals Corporation: Speakers Bureau.

Description: Introduction: Hematopoietic cell transplantation (HCT) advances in reduced intensity conditioning, donor identification, and supportive care have led to its increased use over the last few decades. HCT is a complex process that requires coordination at multiple levels, and there may be disparities in its utilization. To better understand these access disparities, we conducted a systematic review of studies that assessed barriers to referral and/or receipt of HCT. Additionally, we focused on a subgroup of older patients (aged ≥65 at transplant), who we hypothesized would be at higher risk for access barriers to HCT. Methods: A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched for articles published in English from PubMed, Embase, Cumulative Index for Nursing and Allied Health, and Cochrane Central Register of Controlled Trials between the database inception and January 12th, 2018. Inclusion criteria were: 1) clinical trials, observational, qualitative, cross-sectional, or mixed-method study designs; 2) study assessed barriers to HCT or factors associated with referral for or receipt of HCT (except for country-specific economic factors as these are less likely to be targetable), 3) included patients ≥18 years with cancer. Narrative review articles and abstracts without full text were excluded. Two authors independently reviewed all titles and abstracts (N=3,262) and assessed studies for full-text eligibility (N=153). A third reviewer resolved any discrepancies. Eighteen studies met eligibility criteria and an additional 5 studies (not identified on our search strategy) were included on review of the bibliographies. Literature on subgroup of patients aged ≥65 was also assessed. Results: Among the 23 studies included, 16 were published after 2010. Studies were retrospective (N=18; 14 from registry data), cross-sectional (N=4; 2 from registry data), and mixed-method (N=1), and primarily conducted in the US (N=21). Barriers were assessed at the patient level (N=19; sample size ranged from 350 to 38,420), healthcare professional level (N=3; 1 study assessed both patients and healthcare professionals), or country level (N=2). Fourteen studies included some information on age of the patients and 10 studies included some patients aged 60 and above. Seventeen studies only included patients with hematologic malignancies. Age was the most common barrier identified (N=16 out of 16 studies identified older age as a barrier). Fourteen studies showed that older age was associated with lower odds of referral for or receipt of HCT, and the remaining 2 studies provided descriptive data showing lower percentages of patients receiving HCT compared to the younger age groups. Table 1 shows other potential barriers or factors associated with lower referral for or receipt of HCT at the patient, disease, physician, and organizational levels. These included race (N=14 out of 16 studies identified non-white race as a barrier), insurance or financial capacity (N=11/12), comorbidity (N=8/9), gender (N=7/17; primarily female), disease status (N=5/5), patient preferences (N=5/5), time of diagnosis (N=5/5), cancer type (N=4/6), and socioeconomic status (N=4/5). Only one study evaluated factors associated with receipt of HCT in a subgroup of patients ≥65 years. Older age, female gender, and a diagnosis of leukemia other than acute myeloid leukemia were associated with lower odds of receiving HCT. Conclusions: There are limited prospective studies evaluating access barriers to HCT in adult patients with cancer. Older age is the most commonly reported barrier to both autologous and allogeneic HCT, although studies have not addressed specific mechanisms for this disparity. In addition, other potential barriers identified such as gender, race, insurance status, and comorbidity have not been well studied in the context of older age. While some barriers may be difficult to intervene upon (e.g. comorbidity, disease status, performance status), many are amenable to interventions (e.g. socioeconomic status, distance to transplant center, social support). With the increasing trend for HCT in older patients, there is a critical need for prospective studies that better describe these access barriers and their mechanisms in order to design future interventions to reduce disparities in HCT access. Figure. Figure. Disclosures Liesveld: Onconova: Other: DSMB; Abbvie: Honoraria. Aljitawi:Medpace: Consultancy; The University of Rochester Medical Center: Patents & Royalties: Pending patent related to decellularized Wharton's jelly matrix. Klepin:Genentech Inc: Consultancy. Stock:Jazz Pharmaceuticals: Consultancy. Wildes:Janssen: Research Funding. Majhail:Incyte: Honoraria; Anthem, Inc.: Consultancy; Atara: Honoraria.