Abstract: Comorbidity assessment before allogeneic haematopoietic cell transplantation (allo‐HCT) is essential for estimating non‐relapse mortality (NRM) risk. We previously developed the Simplified Comorbidity Index (SCI), which captures a small number of ‘high‐yield’ comorbidities and older age. The SCI was predictive of NRM in myeloablative CD34‐selected allo‐HCT. Here, we evaluated the SCI in a single‐centre cohort of 327 patients receiving reduced‐intensity conditioning followed by unmanipulated allografts from HLA‐matched donors. Among the SCI factors, age above 60, mild renal impairment, moderate pulmonary disease and cardiac disease were most frequent. SCI scores ranged from 0 to 8, with 39%, 20%, 20% and 21% having scores of 0–1, 2, 3 and ≥4 respectively. Corresponding cumulative incidences of 3‐year NRM were 11%, 16%, 22% and 27%; p  = 0.03. In multivariable models, higher SCI scores were associated with incremental risks of all‐cause mortality and NRM. The SCI had an area under the receiver operating characteristic curve of 65.9%, 64.1% and 62.9% for predicting 1‐, 2‐ and 3‐year NRM versus 58.4%, 60.4% and 59.3% with the haematopoietic cell transplantation comorbidity index. These results demonstrate for the first time that the SCI is predictive of NRM in patients receiving allo‐HCT from HLA‐matched donors after reduced‐intensity conditioning.

Abstract: Background: Hepatic SOS is a serious complication after allogeneic HSCT. It has been reported elsewhere that in the period between 1979-2007, the overall mean incidence of hepatic SOS was 13.7% (95%CI:13-15). While prophylactic procedures are widely used, there is no uniform consensus on the optimal strategy for the prevention of this disease. Low dose UFH have been used but its benefit in the prevention of SOS and the potential associated risk of serious bleeding complications have not been fully established. Methods: We evaluated 730 adult allograft recipients transplanted 01/2003-12/2013 for hematologic malignancies [401 (55%) acute leukemia/ MDS, 235 (32%) lymphoma, 64 (9%) multiple myeloma, 30 (4%) CML/myeloproliferative disorder]. The majority received myeloablative conditioning (n = 466, 65%) with either total body irradiation-based (n = 243) or busulfan-based (n = 233), followed by non-myeloablative conditioning (n = 143, 19%) and reduced intensity (RIC) (n = 111, 15%). Approximately half of the patients had T-cell depleted (TCD) grafts (402, 55%). All patients had SOS prophylaxis with low dose heparin 100 units/kg given as continuous IV over 24 hours from admission to day +21 or engraftment. Prior allogeneic HSCT, non-malignant or refractory disease, dual prophylaxis with UFH/ursodiol or therapeutic anticoagulation at the time of allograft admission were all excluded. Results: The median age was 51 (range 21-65) years, and 415 (56%) were male. During the 10 year study period only 15 patients developed hepatic SOS with a day 100 incidence of 2% (95%CI:1-3). When evaluated by conditioning intensity, myeloablative and reduced intensity conditioning recipients had a day 100 incidence of 3% (95%CI:2-4) (Figure) whereas none of the NMA recipients developed SOS. Univariate analysis showed that age, HLA-match, previous hepatitis B or C exposure did not influence SOS development (Table). There was a significantly higher incidence of hepatic SOS in recipients of unmodified (3%) versus TCD grafts (1%), p= 0.025. The median time to SOS onset was 29 days (range 5-57). Six patients received supportive care only whereas 9 had defibrotide therapy. Of those, 7 patients developed severe SOS resulting in multi-organ failure (5 supportive care, 2 defibrotide). Four of 15 patients diagnosed with hepatic SOS are alive at last follow up (7 deaths attributed to SOS). Bleeding complications occurred in 26/730 patients (4%) of which only 4 (0.5%) patients had significant grade 3-4 bleeding. The day 100 grade II-IV and III-IV acute liver GVHD is 2% (95%CI:1-3) and 0.5% (95%CI:0.2-1), respectively. The incidence of day 100 TRM was 9% (95%CI:7-11) for the entire cohort of patients. Conclusion: To our knowledge, this is the largest analysis evaluating the use of low dose UFH for the prevention of hepatic SOS. We demonstrated that UFH prophylaxis is associated with a low incidence of hepatic SOS, is well tolerated, and severe bleeding complications are uncommon. Low dose UFH may be consider as a strategy for the prevention of hepatic SOS in selected patients. Further prospective studies comparing UFH to other hepatic SOS prophylaxis methods are warranted. Table. Univariate analysis of variables potentially associated with day 100 SOS. Variable (95% CI) p-value Age (years) 0.745 〈 40 2% (1-6) ≥ 40 2% (1-3) HLA-match 0.857 8/8 2% (1-4) ≤ 7/8 2% (1-5) Graft 0.025 TCD 1% (0.3-2) Unmodified 3% (2-6) Conditioning regimen 0.054 Myeloablative/RIC 3% (2-4) Non-Myeloablative 0 (NA) Myeloblative conditioning type 0.353 Busulfan-based 2% (1-5) TBI-based 3% (2-6) Hepatitis B & C Serologies 0.089 Negative 2% (1-3) Positive 8% (0.4-30) Figure 1. Figure 1. Disclosures Bhatt: Spectrum: Consultancy. Off Label Use: Use of low dose unfractionated heparin for the prevention of hepatic SOS. van den Brink:Boehringer Ingelheim: Consultancy, Other: Advisory board attendee; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria; Merck: Honoraria; Tobira Therapeutics: Other: Advisory board attendee. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding.

Abstract: Introduction While DCBT provides high rates of sustained donor engraftment, delayed neutrophil recovery is frequent and associated with increased transplant-related mortality. Methods We are investigating the combined transplantation of a 4-6/6 double-unit CB allograft with CD34+ selected haplo-identical PBSC (haploCD34+) to speed myeloid recovery in patients (pts) with high-risk hematologic malignancies. This analysis evaluates sustained neutrophil recovery, engraftment patterns, and potential factors associated with haplo-rejection in 36 DCBT-haploCD34+ recipients. Results 36 DCB-haplo-CD34+ pts (median 48 years, range 16-69) were transplanted 9/2012-6/2014. Diagnoses included 28 acute leukemias (24 CR or aplasia, 4 not in CR) and 8 advanced lymphoid malignancies. 2 pts had had a prior allograft. Conditioning was myeloablative (2 high-dose TBI, 34 reduced intensity) with CSA/MMF and no ATG. CB units had a median infused TNC (x 107/kg) of 2.26 (larger unit) & 1.87 (smaller unit), & a median HLA-allele match of 5/8 (range 2-7/8). Haplo-identical donors (median 37 years, range 18-71) had a median HLA-match of 4/8 (range 4-6/8). The median infused haplo-CD34+ dose was 3.1 x 106/kg (range 1.1-7.5). The median infused haplo-CD3+ dose was 1.5 x 103/kg (range 0.3-8.0). One patient died early post-transplant (multiorgan failure). In 35 evaluable pts, engraftment patterns [groups (Gp) 1-4] based on count recovery & chimerism are shown (Table). Overall, 34/35 (97%) pts recovered neutrophils (median day 13, range 11-38) whereas one 2nd allograft pt with donor-specific HLA-Abs (DSA) to haplo & both units had both primary haplo-rejection and CB graft failure (GF, Gp 4). Additionally, one pt (Gp 4) with transient haplo-mediated neutrophil recovery had subsequent CB GF in the setting of low CD34+ dose in the dominant unit. Both GF pts were salvaged with single-unit CBT. In other pts, haplo-rejection was universal & was associated with dominant CB unit derived T-cell engraftment although rejection speed varied, low haplo dose may have contributed in 2 pts, and 3 of 4 pts overall with haplo-DSA had no haplo-engraftment. Table Engraftment Pattern(n = 35) Median (range)Haplo DoseCD34+ x 106/kg Median (range) 8 Allele HLA-match: Haplo-PatientHaplo-Dominant CB N with DSAto Haplo/ CBs Median (range)Dominant CB CD34+ Dosex 105/kg 1) CB engraftment with haplo bridge (no recurrent neutropenia) N = 18 (51%) Median ANC 12 days, (range 11-14) 3.14 (2.86-5.62) Haplo-patient: 4/8 (4-6/8) Haplo-dom. CB: 4/8 (range 1-7/8) 1 pt DSA to haplo 1 pt DSA to loser CB 1.14 (0.37-5.66) 2) CB engraftment with transient haplo (2nd nadir) N = 5 (14 %) Median ANC 14 days, (range 11-38) 3.0 (2.56-7.46) Haplo-patient: 4/8 (all 4/8) Haplo-dom. CB: 2/8 (2-4/8) None 0.46 (0.25-1.00) 3) CB engraftment with no haplo N = 10 (29%) Median ANC 26 days, (range 15-33) 3.00 (1.05-5.29) Haplo-patient: 4/8 (4-5/8) Haplo-dom. CB 3/8 (1-4/8) 2 pts DSA to haplo 1 pt DSA to loser CB 0.85 (0.54-1.39) 4) Graft failure N = 2 (6%) Pt 1: transient haplo/ no CB Pt 2: no haplo/ no CB Pt 1: 5.06 Pt 2: 4.64 Haplo-patient: Pt 1: 4/8. Pt 2: 5/8 Haplo-dom. CB: Pt 1: 4/8. Pt 2: 4/8 Pt 2: DSA to haplo, dom. CB & losing CB Pt 1: 0.22 Pt 2: 1.27 Of 35 evaluable pts, 27/35 (77%) developed pre-engraftment syndrome (PES, fever 〉 38.3°C not due to infection +/- rash, capillary leak) at a median 10 day onset (range 7-14). PES occurred in 11/18 (61%) Gp 1 pts with robust haplo myeloid bridge vs 16/17 (94%) Gp 2-4 pts with rapid haplo-rejection. Overall, 3/27 (11%) PES pts required ICU care although marked improvement was associated with corticosteroids. Conclusions: DCBT-haploCD34+ is feasible & neutrophil engraftment is enhanced. However, given the haplo-graft can be rapidly rejected, and sustained engraftment is not guaranteed, the quality & dose of the CB unit(s) in this platform is critical. Preliminary analysis suggests the haplo-graft dose & haplo-DSA may be relevant in haplo engraftment whereas there is a high degree of dominant CB unit-haplo HLA-mismatch and its role is unclear. Finally, PES may be more common with prompt haplo-rejection, may be clinically severe, and mandates early diagnosis and pulse corticosteroids. Analysis of serial cytokine samples to further investigate PES biology is ongoing. Disclosures No relevant conflicts of interest to declare.

Abstract: Adoptive immunotherapy with transplant donor-derived virus-specific T-cells is effective in the treatment of CMV viremia and disease complicating allogeneic hematopoietic stem cell transplant (HCT), but is not available if the donor is seronegative or unavailable to provide lymphocytes. In addition, CMV-specific T-cell lines (CMV-CTLs) from non-identical donors may be restricted by HLA alleles not shared by the patient, rendering them ineffective. This limitation has become more problematic with increased use of haploidentical HCT donors. We treated 50 transplant recipients with third party donor-derived CMVpp65-specific T-cells between 10/14/11 and 11/28/16, evaluable for response assessment as of 6/20/17. Patients had received an unmodified (n=11) or T-cell depleted HCT (n=33) or a cord blood (n=6), transplant. Fifteen were treated for overt CMV disease involving CNS (N=6) GI (N=10) and Lung (N=2) and 35 for CMV viremia persisting despite & gt;2 weeks of induction therapy with 1-3 antiviral agents. Treatment with CMVpp65-CTLs was initiated at a median of 151 (29-4940) days post transplant and 128 (7-564) days after CMV reactivation. One patient was treated for CMV colitis developing more than 10 years after transplant due to immune suppression for chronic graft versus host disease. Patients had received a median of 3 (1-6) prior antiviral treatments. Third party CMVpp65-CTLs were selected from a bank of 186 lines generated under GMP conditions from normal HCT donors who specifically consented to use of their T cells in patients other than their designated transplant recipient. Selection was made on the basis of HLA restriction by at least one HLA allele shared by the patient and HCT donor, and matching for & gt; 2/10 recipient alleles. If such a line was not available, a patient could be treated with a line matched at only one HLA allele as long as the restriction was through that matched allele. Patients received 3 weekly infusions of approximately 1x106 CMVpp65-CTL/kg/infusion. Patients were sequentially evaluated for clinical and radiographic changes, quantifications of CMV DNA by PCR and IFN+ CMVpp65-specific T-cells in the blood. Responses were assessed 28-42 days after the first of each cycle of CMVpp65-CTLs. Response in patients with CMV disease was considered complete (CR) if all sites were cleared of virus by biopsy and blood sampling and partial (PR) if symptoms resolved and viremia met criteria of PR. In patients treated for persistent viremia, responses were complete if CMV DNA was cleared in repeated testing, and partial if the level of CMV fell based on the testing method by & gt;50% (N=2) or by 2log10 (N=12). Of the 50 patients 18 had a complete and 14 a partial response for an overall response rate of 64%. Response rates in patients with disease (5CR+4PR/15) were similar to those of patients with persistent viremia (13CR+10PR/35). In patients treated for viremia alone, survival at 6 months was 65.7% and in those with disease 60.0% (a). More extensively pretreated patients who received CMVpp65 CTLs & gt; 100 days post CMV initial detection fared as well as those treated earlier (62.1% vs. 66.7% OS) (b). Patients who responded to CMVpp65-CTL therapy (CR or PR) had an improved survival with 6 month overall survival of 81.3% (b) and 12 month overall survival of 62.1% (c); only 1 of these 32 patients died of CMV. In contrast 7 of 18 non-responding patients died of CMV; overall survival in this cohort was 33.3% at 6 months. By 12 months, 8 non-responding patients had died of CMV and overall survival had decreased to 22.2%. Toxicities associated with CMVpp65-CTL infusions in this cohort are limited with 5 patients experiencing adverse events of & gt; grade 3 severity deemed possibly related to CMVpp65-CTL therapy. Two of these patients died, one due to sepsis and one due to progression of CMV. This study demonstrates a high response rate among patients with otherwise refractory CMV viremia and disease. The bank of CMVpp65-CTLs can provide an immediate source of HLA partially-matched appropriately restricted T cells for adoptive immunotherapy to treat persistent CMV viremia and CMV disease, including disease isolated to the CNS. The availability of 3rd party CMVpp65-CTLs enables treatment early in the course of disease and may thereby improve response rates while minimizing toxicity from anti-viral therapy. Figure 1 Figure 1. Disclosures Doubrovina: Atara: Consultancy, Research Funding. Hasan: Atara Biotherapeutics: Consultancy, Other: During time of this study, Research Funding; Merck: Employment. Kernan: Gentium: Other: Received grants from Gentium during the conduct of the study and research was supported by The National Cancer Institute of the National Institutes of Health under award number P30 CA 008748, Research Funding. Koehne: Atara: Consultancy, Patents & Royalties. O'Reilly: Atara: Patents & Royalties, Research Funding.

Abstract: Older patients are at increased risk for complications and death following allogeneic hematopoietic cell transplantation (allo-HCT). Traditional transplant-specific prognostic indices such as hematopoietic cell transplant comorbidity index (HCT-CI) may not capture all underlying geriatric vulnerabilities, and in-depth evaluation by a geriatrician prior to transplant may not always be available. We hypothesize that routine pre-transplant assessments by interdisciplinary clinical providers including advanced practice providers, nursing staff, physical therapists, occupational therapists, and dietitians, as well as common laboratory tests, may uncover additional geriatric deficits. Using an institutional database and the electronic medical records of 406 adults age 60 years and older (range 60-78.7) who underwent first allo-HCT for hematological malignancies from 2010 to 2016, we examined the prevalence and the prognostic impact of pre-transplant geriatric deficits identified by interdisciplinary clinical providers including geriatric domains of functional activity, cognition, medication, nutrition, and mobility (Table 1), and by routine laboratory tests. With a median follow-up of 39 months for survivors, the 3-year probability of overall survival (OS) and progression-free survival was 47% (95% CI 42-53) and 40% (95% CI 35-45), respectively. The 2-year cumulative incidence of non-relapse mortality (NRM) was 26% (95% CI 22-29). Among pre-transplant geriatric and laboratory variables, we found that impairment in instrumental activities of daily living (IADL) and pre-transplant ferritin level ≥1200 was independently associated with increased NRM and inferior OS. In the multivariate analysis, HCT-CI ≥3, IADL impairment, ferritin level ≥1200, and Karnofsky Performance Scale (KPS) 〈 90 are predictive of NRM (Table 2). Similarly, IADL impairment, ferritin level ≥1200, and high/very high modified disease risk index predict OS (Table 2). Most importantly, the combination of either IADL impairment or ferritin ≥1200 with HCT-CI further stratifies NRM and OS into distinct risk categories, including a group of highly vulnerable, high risk patients with high HCT-CI (≥3) plus IADL impairment and/or ferritin level ≥1200 (Figure 1). Detailed examination of non-relapse death among all vulnerable patients (≥2 risk factors) reveals a higher proportion of death from organ toxicities than patients with zero or 1 risk factor. Our findings establish a rapid and simple assessment tool to risk stratify older patients prior to allo-HCT. While requiring validation, the geriatric vulnerability index can be easily completed and integrated into outpatient clinics and the electronic medical record. It may also provide an entry point for prospective, interventional trials aimed at reducing non-relapse mortality and toxicities, and at improving survival and quality of life of older allo-HCT patients. Disclosures Perales: Takeda: Other: Personal fees; Merck: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Abbvie: Other: Personal fees; Novartis: Other: Personal fees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy.

Abstract: While there has been significant increase in the number of older patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT), the prevalence and the impact of geriatric syndromes associated with allo-HCT remains unknown. Using an institutional database and the electronic medical record, we retrospectively examined the incidence, predictive factors, and the impact of common geriatric syndromes of delirium, urinary incontinence, pressure ulcer, and mechanical fall among 527 patients age 60 and above (range 60-78.7) who underwent first allo-HCT for hematological malignancies at our institution from 2001 to 2016. We hypothesize that allo-HCT-associated geriatric syndromes negatively impact non-relapse mortality and overall survival. We identified all relevant geriatric events from the start of the conditioning regimen to 100 days post stem cell infusion. Among common geriatric syndromes, we found that delirium had the highest 100-day cumulative incidence at 21% (95% CI 18-25), followed by falls at 7% (95% CI 5-9) (Figure 1). There were only 11 incidences of new urinary incontinence and 3 incidences of new pressure ulcers. With a median follow-up of 46 months for survivors, the 3-year probability of overall survival and progression-free survival is 47% (95% CI 42-51) and 40% (95% CI 36-44), respectively (Figure 1). The 2-year cumulative incidence of non-relapse mortality is 28% (95% CI 24-32). We assessed the association of standard, pre-transplant patient demographic, clinical, geriatric, and laboratory characteristics with the cumulative incidence of delirium and fall. We found that prior fall within last year, potentially inappropriate medications use prior to transplant admission (defined by 2015 American Geriatric Society updated Beers criteria), platelet count 〈 50 k/µl, creatinine clearance 〈 60 ml/min predicted delirium in the multivariate analysis. Age over 70 and impaired activities of daily living (ADL) predicted fall in the multivariate analysis with prior fall within last year close to be a significant variable (Table 1). We next investigated the impact of delirium and fall on transplant outcomes. Delirium, but not fall, is independently associated with significantly increased risk of death at 100 days adjusted for standard transplant variables (OR 6.3, 95% CI 3-13.4, p 〈 0.001). In addition, patients who experienced delirium and fall during their initial transplant admission had significantly increased length of stay (11 and 15 days longer, respectively, both p 〈 0.001). In a landmark analysis of 100-day post-transplant survivors, both delirium and fall are associated with significantly increased long-term non-relapse mortality, with hematopoietic cell transplantation comorbidity index (HCT-CI) as an additional significant predictor (Table 2). While limited by the retrospective design and likely under-reporting, our findings establish for the first time the baseline incidence and predictors of common geriatric syndromes associated with allo-HCT. Importantly, we have demonstrated significant negative impact of delirium and fall on the short- and long-term transplant-associated mortality and morbidities. The temporal pattern and impact of geriatric delirium and fall warrants preemptive, targeted, longitudinal, and multidisciplinary interventions to improve transplant outcomes and to expedite functional recovery after allo-HCT for older patients. Disclosures Perales: Takeda: Other: Personal fees; Novartis: Other: Personal fees; Abbvie: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy.

Abstract: Background : While dCBT is associated with high rates of sustained donor engraftment, delayed neutrophil recovery in adults is frequent and can contribute to extended hospitalization and early transplant-related mortality. Methods : We investigated engraftment after myeloablative dCBT supplemented with CD34+ selected haploidentical PBSC (haploCD34+) in patients (pts) with high risk hematologic malignancies or aplastic anemia in a phase II clinical trial. The aim was to abrogate neutropenia (ANC 〉 /= 500 within 14 days) with a haplo myeloid bridge prior to CB engraftment. Pts did not receive ATG due to the increased mortality risk reported in adult CBT. Double unit CB grafts allowed comparison to dCBT controls without haploidentical graft supplementation. Results : 78 adult pts [median age 48.5 years (range 21-68), median weight 82 kgs (range 48-138), 44 (56%) CMV+, 3 with prior allografts] underwent haplo-dCBT between 9/2012-12/2017. Diagnoses included 54 (69%) acute leukemias, 10 (13%) MDS/ MPN (all ≤ 10% blasts at work-up), 10 (17%) NHL/ HD and 1 aplastic anemia. Conditioning was myeloablative (1 Cy 120/ Flu 75/ TBI 1375, 77 intermediate intensity Cy 50/ Flu 150/ Thio 5-10/ TBI 400) with CSA/ MMF. CB units had a median infused TNC of 2.3 (range 1-5.7) x 107/kg/unit & median infused viable CD34+ cell dose of 1.1 (range 0.1-3.1) x 105/kg/unit with a median 5/8 (range 2-7) unit-recipient HLA-allele match. Haplo CD34+ grafts [procured from children (46%), siblings (31%), parents (13%) or extended family (10%)] had a median infused CD34+ dose of 5.2 x 106/kg (range 1.1-16.8) and a median infused CD3+ dose of 1.6 x 103/kg (range 0.3-13.7). Sixty-one (78%) haplos were 4/8 and 17 (22%) were 5-7/8 HLA-matched to the pt. In 77 evaluable pts (1 pt died on day 14), 4 engraftment patterns were observed (Table 1). All but 2 pts had sustained CB engraftment with either an optimal haplo-bridge (Gp. 1, 34/77, 44%), a transient bridge with a second nadir preceding CB engraftment (Gp. 2, 20/77, 26%), or no bridge (Gp. 3, 21/77, 27%). The 2 remaining pts had CB/ haplo graft failure (Gp. 4, 2/77, 3%); both were successfully re-transplanted with single CB units. While there was no difference in the day 100 TRM in the 34 optimal bridge pts vs pts with transient or no bridge [9% (95%CI 2-21) vs 15% (95%CI 6-27), p = 0.388] , optimal bridge pts had faster platelet recovery [19 (range 14-41) vs 44.5 days (range 14-67)] and earlier hospital discharge [28.5 (range 20-60) vs 36 days (range 28-98)] . Similar to dCBT alone, chimerism analysis revealed sustained engraftment in haplo-dCBT is mediated by a "winning" CB unit. This was heralded by winning unit-derived T-cells seen as early as day +28. Although universal, the speed of haplo rejection varied, and a high haplo chimerism percentage early post-transplant did not guarantee successful bridging. Analysis of factors potentially predicting an optimal bridge is shown in Table 2. The median winning CB unit-haplo 8-allele HLA-match was 3/8 (range 1-7/8). In univariate analysis, higher haplo CD34+ dose/kg, 〉 4/8 haplo-recipient HLA-match and ≥ 3/8 winning unit-haplo HLA-match were associated with a higher likelihood of bridging. Haplo CD34+ dose and winning unit-haplo HLA-match remained significant in multivariate analysis. Conclusions: While haplo-dCBT can be associated with enhanced neutrophil recovery, this platform does not guarantee a successful myeloid bridge due to early haplo rejection by the winning CB unit. This universal haplo rejection highlights the importance of the CB graft dose and quality with this ATG-free strategy as the CB will mediate sustained engraftment. Our findings have significance for strategies that combine unmanipulated CB with any third-party or ex vivo expanded T-cell depleted product given higher product CD34+ cell dose and better HLA-match to the unmanipulated CB unit could improve the likelihood of successful myeloid bridging. The data also support alternative approaches to improve myeloid recovery after CBT such as optimized unit selection and vivo expansion. Disclosures O'Reilly: Atara Biotherapeutics: Consultancy, Patents & Royalties, Research Funding. Perales:Takeda: Other: Personal fees; Novartis: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees; Abbvie: Other: Personal fees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Shah:Janssen: Research Funding; Amgen: Research Funding.

Abstract: Double-unit CB transplantation (DCBT) has provided high rates of sustained donor engraftment in patients with hematologic malignancies. However, delayed engraftment is frequent with a median neutrophil & platelet recovery of 25 & 48 days, respectively, in adult DCBT recipients at our center. This delay is associated with increased transplant-related mortality (TRM). It is also associated with prolonged hospitalization with a median discharge time of +42 days (range 25-76) in recent adult myeloablative DCBT recipients. Methods We investigated the combined transplantation of a 4-6/6 HLA-A,-B antigen, -DRB1 allele matched double-unit CB allograft (infused on day 0) with peripheral blood stem cell derived Miltenyi column selected haplo-identical CD34+ cells (haplo-CD34+, infused on day 0 or +1) to speed myeloid recovery. We used DCB grafts to facilitate comparison with historic/concurrent DCB controls transplanted without haplo-CD34+. Results Of 23 protocol eligible patients, 6/23 (26%) underwent DCBT only due to the lack of any suitable haplo-identical donor. Thus, 17 patients [median 39 years (range 16-69), median 78 kg (range 63-133)] were transplanted 9/2012-6/2013 with DCB plus haplo-CD34+ cells for high-risk hematologic malignancies. Diagnoses included 12 acute leukemias & 5 lymphomas. Conditioning was myeloablative with CSA/MMF immune suppression & no ATG. Median infused CB TNC x 107/kg was 2.29 (larger unit, range 1.73-2.95) & 1.82 (smaller unit, range 1.26-2.48). Haplo-identical donors (median 37 years, range 19-71) had a median donor-recipient HLA-match of 5/10 (range 5-7). 15 patients received the targeted infused haplo-CD34+ cell dose of 3 x 106/kg whereas 2 each received haplo-CD34+ cell doses of 1 x 106/kg. The median infused haplo-CD3+ dose was 0.6 x 103/kg (range 0.3-1.6). One patient died on day 14. Of 16 remaining evaluable patients, all (100%) engrafted with a median neutrophil recovery of 13.5 days (range 11-31) in 14 patients who received 3 x 106/kg haplo-CD34+ cells, and 26 and 18 days in the 2 patients who received 1 x 106/kg haplo-CD34+ cells. Platelet recovery ≥ 20 × 109/l has occurred in 12/15 patients (median 27 days, range 18-46) to date. Serial chimerism results demonstrating the contribution of haplo-CD34+ cells & each CB unit to date is shown (Table). While myeloid recovery on day 14 was predominantly haplo-CD34+ cell mediated, one CB unit dominated by day 28 in both neutrophil & T-cell subsets. The median total donor chimerism was 100% the dominant CB unit by day 100. With a median follow-up of survivors of 5 months (range 1-10), to date 9 of 15 evaluable patients have developed grade II-IV aGVHD by day 100 (7 grade II, 1 grade III, 1 grade IV). One patient with refractory leukemia transplanted with disease has relapsed, & 4 have died of TRM (2 organ failure, 1 grade IV aGVHD, 1 CMV infection). Excluding early deaths, of patients who were discharged in the first 100 days (n = 13), the median day of discharge was day +33 (range 21-60). Conclusions Double-unit CBT supplemented by haplo-CD34+ cells is safe. The incidence of neutrophil engraftment is high & the speed of neutrophil recovery is enhanced compared with recent DCBT controls. A shorter time of initial hospitalization (9 days) has offset the cost of the addition of haplo-CD34+ cells. It is intriguing that the dominant CB unit can rapidly reject the haplo-identical donor. This may be facilitated by omission of ATG, and the determinants of the speed of haplo-donor rejection are under investigation. Whether the same results could be achieved with a single CB unit plus haplo-CD34+ cells requires investigation. Addition of haplo-CD34+ cells is also an alternative to expansion, although expansion remains an important strategy to augmenting myeloid recovery given some patients do not have any suitable haplo-identical donors. Disclosures: No relevant conflicts of interest to declare.

Abstract: Background: Measurable residual disease (MRD) is a powerful prognostic factor in AML, including in prediction of outcomes post allogeneic stem cell transplant (alloSCT). However, genomic predictors of successful MRD eradication with chemotherapy prior to alloSCT are unclear. Objectives: Here we provide an integrated analysis of 233 patients (pts) who underwent induction chemotherapy with baseline next-generation sequencing (NGS) followed by serial immunophenotypic monitoring for MRD while patients received additional therapy and alloSCT. Methods: All pts who received anthracycline + cytarabine, +/- investigational agents at Memorial Sloan Kettering Cancer Center starting in April 2014 were retrospectively studied (A). 142 out of 233 pts subsequently underwent alloSCT after induction or additional therapy (A). Immunophenotypic MRD was identified in bone marrow aspirates (BMA) by multiparameter flow cytometry. Any level of residual disease was considered MRD+. Molecular analysis was obtained from pre-induction BMA by NGS using 28 or 49 or 400 gene panels. Results: Patient and treatment characteristics for all pts are detailed in panel (B). Induction chemotherapy resulted in an MRD-CR/CRi and MRD+CR/CRi in 29% and 23% of all pts, respectively (C). Additional therapy included consolidation (n=51), intensive re-induction/salvage (n=47) and non-intensive therapy (n=9). Of 83 AML pts with persistent AML and 58 pts with MRD+CR/CRi after induction (R1), 38/141 (27%) were able to be converted to MRD-CR/CRi. While 33/38 of pts went on to alloSCT after conversion to MRD-CR/CRi, 22 and 36 pts went to alloSCT with persistent AML and MRD+CR/CRi AML, respectively. We focused on pre-induction molecular predictors for achieving an MRD-CR/CRi response prior to transplant for the 142 pts who underwent alloSCT (D). Pts with a NPM1 (79%, Odds ratio [OR] 3.7, p=0.01), IDH1 (92%, OR 3.9, p=0.01) and KRAS (100%, OR 5.0, p=0.03) mutations achieved high rates of MRD-CR/CRi prior to alloSCT. In contrast, RUNX1 (28%, OR 0.2, p=0.01), TP53 (12%, OR 0.1, p=0.02) and SF3B1 (14%, OR 0.1, p=0.04) mutations predicted decreased odds of achieving MRD-CR/CRi prior to alloSCT despite induction and post-induction therapy. AlloSCT resulted in high rates of conversion from MRD+ and persistent disease to MRD negativity. Most pts who entered transplant with CR/CRi MRD+ (28/36, 76%) or persistent AML (14/22, 64%) cleared MRD by the first post-transplant BMA at a median of 32 days (E). Post-alloSCT follow-up indicated value in converting MRD+ to MRD- prior to alloSCT. There was no significant difference in post-transplant cumulative incidence of relapse (F) and OS (G) between early MRD-CR/CRi immediately following induction versus later conversion to MRD-CR/CRi with additional therapy prior to alloSCT. Despite initial post-transplant MRD clearance, pts who entered alloSCT with persistent AML or MRD+ had higher incidence of relapse (p=0.00037, F) and poorer post-transplant OS (p=0.013, G) compared to pts who entered alloSCT with MRD-. Pts with persistent disease prior to alloSCT had shorter duration of MRD- induced by alloSCT compared to pts with MRD-CR/CRi after induction or converted MRD-CR/CRi prior to alloSCT (p=0.0042, H). Importantly, duration of MRD negativity after alloSCT for patients who achieved MRD- prior to alloSCT was not affected by whether patients received induction +/- consolidation (I: treatment type 1-3 from B) vs. induction and salvage treatment for refractory AML (I: treatment type 4-6 from B). Conclusion: We show that transplanted AML pts with specific molecular mutations (RUNX1, SF3B1, and TP53) are unlikely to achieve MRD-CR/CRi after induction, consolidation or salvage therapy, while other mutations (NPM1, IDH1, KRAS) predict high rates of MRD- prior to alloSCT. Additional post-induction therapy may be advantageous for some MRD+ pts to achieve MRD- prior to alloSCT. Post-transplant OS is improved in pts who are MRD- at time of transplant, regardless of whether they required additional therapy beyond induction to achieve this state. AlloSCT is highly effective at eradicating MRD, but post-transplant MRD- is more durable in pts who are MRD- pre-alloSCT. Our results suggest that development of MRD-eradicating therapies has the potential to improve post-transplant outcomes and argues for innovative trials for pts with adverse molecular features currently unlikely to achieve MRD- pre alloSCT. Figure Disclosures Cai: Imago Biosciences, Inc.: Consultancy, Current equity holder in private company; DAVA Oncology: Honoraria. Geyer:Amgen: Research Funding. Glass:Gerson Lehman Group: Consultancy. Stein:Syros: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotheryx: Consultancy; Bayer: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Seattle Genetics: Consultancy; Abbvie: Consultancy; Amgen: Consultancy; Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Levine:Gilead: Honoraria; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Qiagen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; Lilly: Consultancy, Honoraria; Imago: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Novartis: Consultancy; Prelude Therapeutics: Research Funding; Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Morphosys: Consultancy; Roche: Consultancy, Honoraria, Research Funding. Gyurkocza:Actinium: Research Funding. Perales:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; NexImmune: Membership on an entity's Board of Directors or advisory committees; Cidara Therapeutics: Other; Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Abdel-Wahab:H3 Biomedicine Inc.: Consultancy, Research Funding; Janssen: Consultancy; Envisagenics Inc.: Current equity holder in private company; Merck: Consultancy. Papaemmanuil:Kyowa Hakko Kirin: Consultancy, Honoraria; Isabl: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; MSKCC: Patents & Royalties; Novartis: Consultancy, Honoraria; Illumina: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Prime Oncology: Consultancy, Honoraria. Giralt:KITE: Consultancy; NOVARTIS: Consultancy, Honoraria, Research Funding; OMEROS: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding; TAKEDA: Research Funding; ACTINUUM: Consultancy, Research Funding; MILTENYI: Consultancy, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria. Tallman:Glycomimetics: Research Funding; Rafael: Research Funding; Amgen: Research Funding; Bioline rx: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Rigel: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Membership on an entity's Board of Directors or advisory committees; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Orsenix: Research Funding; Cellerant: Research Funding; Abbvie: Research Funding. Goldberg:AROG: Research Funding; Aprea: Research Funding; ADC Therapeutics: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; Pfizer: Research Funding; Celularity: Research Funding.