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The α4s7 integrin is upregulated on naive and memory T cell subsets in patients who subsequently develop gastrointestinal (GI) acute GVHD. Natalizumab (Tysabri®, Biogen Inc.) acts against the α4 subunit that mediates homing of lymphocytes to the GI tract. We initiated a phase II study of natalizumab with corticosteroids for initial treatment of acute GI GVHD. In total, 300 mg IV of natalizumab was given, with steroids initiated up to 3 days prior. Twenty-one subjects were treated, median age was 63 years (range 38–74), and 15 (71%) were male. Eighteen (86%) underwent RIC, 15 (71%) received MUD, and all received PBSCs. Overall GVHD at enrollment was grade II in 4 and grade III in 17. The primary endpoint, day 56 GVHD-free survival rate, was attained in 33.3%. The overall response rate at day 28 and 56 was 57% and 52%, respectively. Six of eight CRs were durable for 1 year. Five experienced toxicity possibly related to natalizumab and ten had infections before day 100. 2-year OS was 43% (95% CI 22–62%) and 2-year NRM was 52% (95% CI 29–71%). Natalizumab with corticosteroids as initial treatment of acute GI GVHD is safe, effective, and durable.

fludarabine with intravenous busulfan at doses of 3.2 mg/kg (Flu/Bu1) or 6.4 mg/kg (Flu/Bu2). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication of hematopoietic stem cell transplantation (HCT) that is felt to be triggered, at least in part, by damage to the liver sinusoidal endothelium from cytotoxic conditioning regimens. Accordingly, the incidence of VOD/SOS after reduced-intensity conditioning (RIC) HCT is low compared with myeloablative transplantation, and the natural history, risk factors, and outcomes of VOD/SOS after RIC have not been well characterized. We retrospectively reviewed 1583 consecutive patients receiving RIC HCT at the Dana-Farber Cancer Institute between 2007 and 2017 and ascertained 26 cases of VOD/SOS. The median day of VOD/SOS onset was 26 days (range, 5 to 48) and the cumulative incidence at day 50 was 1.6% (95% confidence interval [CI], 1.1% to 2.4%). Day 100 nonrelapse mortality rate was 23% in the VOD/SOS cohort compared with 6.4% in patients without VOD/SOS (P = .006). Cumulative incidence of VOD/SOS at day 50 was 3.1% after RIC regimen with Flu/Bu2 ± ATG (fludarabine with two doses of busulfan, total dose 6.4 mg/kg, with or without anti-thymocyte globulin), compared with 0.15% after Flu/Bu1 ± ATG (fludarabine with single busulfan dose 3.2 mg/kg, with or without anti-thymocyte globulin) (P = .0002); the incidence rate was 2.1% after RIC HCT with sirolimus-containing graft-versus-host disease prophylaxis, compared with 0.8% for RIC without sirolimus (P = .06). Significant risk factors identified in multivariable analysis for the development of VOD/SOS were sirolimus use (hazard ratio [HR], 5.1; 95% CI, 1.8 to 14.2; P = .002) and RIC regimen with Flu/Bu2 ± ATG (HR, 34; 95% CI, 4.5 to 252; P.001) or other (HR, 32; 95% CI, 3.9 to 257; P = .001) compared with Flu/Bu1 ± ATG. Rising serum tacrolimus or sirolimus levels, new acute kidney injury, and increasing platelet transfusion requirements were significant early predictors of onset in the week preceding prior VOD/SOS diagnosis. When compared with a previously published cohort of 76 patients with VOD/SOS who developed VOD/SOS after myeloablative HCT in the same time period, VOD/SOS after RIC occurred later and was associated with a lower peak bilirubin level and better overall survival. The variability in presenting features for RIC VOD/SOS highlights the importance of maintaining a high index of suspicion for this entity in RIC HCT.

Hepatic veno-occlusive disease (VOD), or sinusoidal obstruction syndrome (SOS), is a serious complication of hematopoietic stem cell transplantation (HSCT) with mortality in its severe form exceeding 80%. Although the incidence of VOD/SOS has fallen with contemporary transplantation practices, the increasing use of inotuzumab, the return of gemtuzumab, and the popularity of pharmacokinetic-guided high-dose busulfan may impact incidence. Early intervention with defibrotide improves survival, but prompt diagnosis can be difficult. We aimed to identify clinical parameters that could aid in early detection of VOD/SOS in a large, retrospective, cohort study. Of the 1823 adult patients who underwent myeloablative HSCT between 1996 and 2015 in our center, 205 (11%) developed VOD/SOS, with a median onset of day +14. We compared parameters in the 7 days preceding VOD/SOS onset for cases to 447 randomly selected control subjects in an analogous time frame to determine those with predictive value. Between 7 days before and the day of diagnosis, VOD/SOS patients had higher serum creatinine levels and were more likely to develop acute kidney injury (61% versus 33%, P.0001), more commonly experienced refractoriness to platelet transfusion (48% versus 24%, P.0001), and had higher trough serum tacrolimus levels (7 days before VOD/SOS onset: median 8.8 versus 7.3, P = .0002; day of onset: median 9.3 versus 7.2, P.0001) compared with control subjects. Acute renal dysfunction, platelet refractoriness, and elevated or abnormal tacrolimus levels are dynamic clinical markers that should alert clinicians to the development of VOD/SOS before the presence of classical diagnostic criteria. Using these clinical features to recognize VOD/SOS earlier in its clinical course could promote earlier treatment and lead to improved outcomes of this potentially serious complication.

With improvement in transplantation practices in the modern era, nonrelapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation (HSCT) has improved, while disease relapse rates have remained unchanged. Survival outcomes are therefore driven by NRM in the modern era. Myeloablative conditioning (MAC) regimens are used to maximize disease control and facilitate engraftment; however, their use is often limited by toxicity. The commonly used MAC regimens incorporate either chemotherapy plus total body irradiation (TBI) or combination chemotherapy. Furthermore, reduced-toxicity myeloablative (RTM) regimens, such as fludarabine/busulfan (FluBu), have emerged as alternatives to traditional MAC and their impact on outcomes in the current era have not been fully investigated. In this study, we compare outcomes following HSCT, using the chemotherapy only RTM MAC regimens FluBu with the chemoradiotherapy regimen cyclophosphamide/TBI (CyTBI), for patients with hematologic malignancies who underwent MAC HSCT at the Dana-Farber Cancer Institute. We hypothesized that the chemotherapy-only regimen would fare better, primarily due to improved NRM. A retrospective cohort analysis was performed on 387 patients with myeloid or lymphoid hematologic malignancies who underwent HLA-matched related (8/8), matched unrelated (8/8), or single-antigen mismatched unrelated (7/8) HSCT following myeloablative conditioning. Patients received FluBu (n = 158) or CyTBI (n = 229). The primary outcome was overall survival (OS) and all other outcomes were regarded as secondary. A subset analysis was performed for patients55 years of age and for acute myelogenous leukemia/myelodysplastic syndrome patients of age 55 years. For the whole cohort, 3-year OS was similar for FluBu compared with CyTBI in unadjusted analysis. However, in multivariable analysis, FluBu resulted in superior OS compared with CyTBI (3-year adjusted estimate: 65% versus 55%, respectively; HR for death, .62; 95% CI, .40 to .97; P = .036). While relapse rates were similar between the 2 regimens, NRM and acute graft-versus-host disease (GVHD) (grade II to IV) were significantly worse with CyTBI compared with FluBu. Rates of chronic GVHD were similar between 2 regimens. These results were consistent in a subset of patients55 years of age and in acute myelogenous leukemia/myelodysplastic syndrome patients below 55 years of age. The RTM chemotherapy-only regimen FluBu appears to be as effective and more tolerable than the chemoradiotherapy regimen CyTBI, leading to better OS driven by better NRM. The improvement in NRM was attributable chiefly to lower rates of grade II to IV acute GVHD. Relapse rates were not increased with FluBu. In the absence of randomized data, FluBu appears to be the optimal regimen for myeloablative HSCT in patients of all age groups.

Introduction: Hepatic veno-occlusive disease (VOD)/Sinusoidal Obstruction Syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT) that is triggered, at least in part, by conditioning regimen-induced sinusoidal endothelial cell injury. VOD is thus commonly, but not exclusively, associated with myeloablative conditioning (MAC). The incidence of VOD in reduced intensity conditioning (RIC) HSCT was ≈2% in a single center series (Carreras et al. BBMT 2011), and risk factors for VOD in RIC HSCT remain poorly defined. Methods: We performed a retrospective review to confirm all cases of VOD among patients undergoing RIC HSCT at the Dana-Farber Cancer Institute/Brigham and Women's Cancer Center between January 2007 and June 2017. Diagnosis of VOD was based on modified Seattle or Baltimore criteria and/or liver biopsy or RUQ ultrasound in conjunction with fluid retention/ascites and hepatomegaly/RUQ pain. Diagnosis dates for all VOD cases were confirmed and clinico-laboratory values collected in the 10 days preceding the diagnosis. The same data were collected for a randomly selected control non-VOD RIC cohort, calculated from the median day of VOD onset derived from the cases. Acute kidney injury was defined as an absolute increase in creatine by 0.3 mg/dL or a relative increase of > 50% within a 48-hour period. Increased platelet transfusion requirement was defined as requiring a platelet transfusion on 2 consecutive days in the 7 days prior to VOD diagnosis, excluding transfusions for procedures. Incidence of VOD at D50 was calculated using a competing risk framework. Cox regression was used to identify significant features for predicting VOD. Survival was compared to a concurrent cohort of 76 patients with VOD after MAC HSCT recently published from our center (Roeker et al. BBMT 2018). Results: A total of 1492 patients underwent RIC HSCT, of whom 1070 (67.8%) received sirolimus (Sir) with tacrolimus (Tac) as part of the GVHD prophylaxis, and 1217 (82%) received intravenous busulfan(Bu) 3.2 or 6.4mg/kg with fludarabine(Flu) as conditioning. Twenty-six developed VOD (median day of diagnosis = d+26, range 5-48 days), for a cumulative incidence of 1.6% (95%CI 1.1%-2.4%). The median bilirubin at diagnosis was 1.1 mg/dL(range 0.6-5.2). Only 5 (19.2%) patients had a bilirubin of ≥2.0 mg/dL on the date of VOD diagnosis, although total bilirubin peaked at ≥ 2 mg/dL in 17 of 26 (65.4%). VOD was mild/moderate in 16 and severe in 10 patients. Sixteen had received ursodiol as VOD prophylaxis. Defibrotide was used as treatment in 17 cases. The 2-year overall survival (OS) was 54% from VOD onset. VOD was associated with increased risk for NRM (HR 4.02, 95% CI 2.1-7.7, p1, increasing platelet transfusion requirements, and increasing Tac and Sir trough levels (Table 1, Fig 1). Conclusions: The incidence of VOD in this large modern cohort of 1492 RIC HSCT patients was 1.6%, and was associated with the use of Sir with Tac. Onset of VOD in RIC patients was delayed (median D+26 vs. D+14) and 2 yr-OS is superior compared to MAC patients. Only 19% of the RIC VOD cases met the bilirubin threshold for Baltimore and Seattle criteria at diagnosis, suggesting that the rise in bilirubin is a later event in these RIC VOD cases, whereas increasing platelet transfusion requirements, sudden rise in Tac and Sir levels, elevated serum creatinine and acute renal injury appear to be early clinical predictors. Disclosures Nikiforow: Kite Pharma: Consultancy. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Ho:Jazz Pharmaceuticals: Consultancy.

Background: Graft-vs.-host disease (GVHD) is caused by allorecognition of host antigens by tissue-specific donor lymphocytes. We have previously demonstrated that α4s7 integrin is upregulated on both naive and memory T cell subsets in patients who subsequently developed intestinal acute GVHD (Chen, BMT 2013). This integrin interacts with endothelial cell adhesion molecules and mediates homing of lymphocytes to the gastrointestinal (GI) tract. Natalizumab (Tysabri®, Biogen Inc.) is a selective adhesion molecule inhibitor, acting directly against the α4 subunit of α4 integrins. Given the poor outcomes of GI GVHD when treated with corticosteroids alone, we initiated a phase II study to determine the safety and efficacy of natalizumab in combination with corticosteroids for the initial treatment of acute GI GVHD. Methods: Subjects with new-onset, acute GVHD of the lower GI tract were eligible to participate. Other organ involvement was permitted but not required. Biopsy confirmation of GI GVHD and exclusion of infectious causes of diarrhea were required. Natalizumab was given at a dose of 300 mg IV, with a second dose permitted 4 weeks later in the event of an incomplete response. An initial corticosteroid dose of 2 mg/kg of methylprednisolone was suggested, but dosing and dose reductions were at the discretion of the treating physician. Steroids could be initiated up to 7 days prior to the initiation of natalizumab while biopsy and infectious disease specimens were being analyzed. The primary endpoint was GVHD-free survival rate 56 days from enrollment. Secondary endpoints included response rates at day 28 and 56, steroid dose at days 28, 56, 100, 180 and 365, incidence of systemic infections at day 56 and 180, and overall survival. Results: 18 subjects were enrolled and received at least one dose of natalizumab. Subjects had a median age of 63.5 years, and 12 were male. Fifteen had a non-myeloablative transplant, 12 had a matched unrelated donor, and all had received PBSCs. All subjects had newly diagnosed acute GI GVHD at time of enrollment; 4 had concomitant cutaneous and 1 had concomitant hepatic involvement. Stage 1, 2, 3, and 4 GI involvement was noted in 7, 4, 4, and 3 subjects respectively, corresponding to overall grade II GVHD in 7 and grade III in 11 subjects. Sixteen patients had data for response assessment. The day 56 GVHD-free survival rate was 37.5%. The overall response rate (PR+CR) for GI GVHD at day 28 and day 56 was 75% and 62.5% respectively. All surviving subjects except one achieved steroid dose reduction by day 56, with a median reduction of 61.6%. Three patients experienced treatment-related toxicity possibly related to natalizumab; one subject had grade 2 hepatic toxicity, one had grade 4 encephalopathy, and one developed hepatic failure. Three subjects have developed chronic GVHD. Four subjects had documented infections with bacteria (2), yeast (1), and viral pathogens (1- polyomavirus). Six subjects had measurable JC viremia prior to initiation of natalizumab and 8 subjects had measurable JC viremia at day 56, although only 1 subject had a viral load greater than 1000 copies/ml. No subject has developed JC-associated disease. Seven subjects have died. Causes of death include GVHD (2), disease relapse (2), and organ failure (3). With a median follow-up of 180 days, the 6 month overall survival was 52% (95% CI 25-74%). Conclusion: Natalizumab in combination with corticosteroids as initial treatment of acute gastrointestinal GVHD is feasible and well tolerated. These early results suggest a higher rate of response at day 56 than is typically observed with steroids alone. Inhibition of T-cell homing to the GI tract may improve GI GVHD response and potentially mitigate progression of acute GVHD. Disclosures Koreth: Kadmon Corp: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy; Prometheus Labs: Research Funding; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Research Funding. Armand: Bristol-Myers Squibb: Consultancy, Research Funding; Tensha: Research Funding; Affimed: Research Funding; Sequenta/Adaptive: Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Roche: Research Funding; Genmab: Consultancy; Pfizer: Consultancy, Research Funding; Infinity: Consultancy; Otsuka: Research Funding; Sigma Tau: Research Funding. Antin: Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Cutler: Pfizer: Consultancy; Pharmacyclics: Consultancy; Kite: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Astellas: Consultancy.