Porter, David L.

CD19-directed CAR T-cells (CTL019) can produce durable remissions in chronic lymphocytic leukemia (CLL), but therapeutic success depends on whether autologous T-cells expand, persist, and retain cytotoxic function after manufacturing. Failure of CLL T-cells is often attributed to exhaustion, although many dysfunctional CLL T-cells retain inflammatory cytokine production. We tested whether this paradox reflects immunosenescence, an aging-like program defined by costimulatory loss, DNA damage, inflammatory secretion, repertoire restriction, and proliferative arrest. In response-linked preinfusion CTL019 products, nonresponders and short partial responders had higher senescence and senescence-associated secretory phenotype (SASP) programs than the functional-responder group, comprising complete responders and partial responders with transformed disease. These programs were detectable before infusion and became more prominent during manufacture in susceptible products. They tracked with weak in vivo CAR T-cell expansion and were associated with inferior survival. Serum proteomics revealed a circulating, CLL-associated SASP-like inflammatory milieu in nonresponders. Flow cytometry and T-cell receptor (TCR) profiling showed that poor responders carried CD27⁻CD28⁻ and KLRG1⁺ CD8 T-cells at apheresis, lower product CD27, and reduced product TCR diversity. Research-manufactured CAR T-cells from treatment-naïve CLL samples displayed the same state, most prominently in CD4 CAR T-cells, with SA-β-gal, p16, p53, DNA damage, depletion of less-differentiated states, and senescence-enriched transcriptomes. Under repeated CD19 stimulation, CLL-derived products reached a proliferative ceiling, and p53-high products lost cytotoxic reserve. Ibrutinib improved proliferative fitness, attenuated senescence-associated features and SASP output in paired patient and direct-exposure assays, and enhanced CAR T-cell expansion in an ibrutinib-resistant CLL model. Together, these data identify immunosenescence as a measurable and functionally consequential barrier to CAR T-cell efficacy in CLL and a candidate for therapeutic modulation.

The recent development and clinical implementation of novel immunotherapies for the treatment of Hodgkin and non-Hodgkin lymphoma have improved patient outcomes across subgroups. The rapid introduction of immunotherapeutic agents into the clinic, however, has presented significant questions regarding optimal treatment scheduling around existing chemotherapy/radiation options, as well as a need for improved understanding of how to properly manage patients and recognize toxicities. To address these challenges, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in lymphoma to develop a clinical practice guideline for the education of healthcare professionals on various aspects of immunotherapeutic treatment. The panel discussed subjects including treatment scheduling, immune-related adverse events (irAEs), and the integration of immunotherapy and stem cell transplant to form recommendations to guide healthcare professionals treating patients with lymphoma.

Abstract Chimeric antigen receptor T cell (CART) therapy has developed as a powerful and potentially curative therapy in hematological malignancies over the last few years. CD19 directed CART cells have resulted in impressive complete response rates of ~90% in acute lymphoblastic leukemia that are durable for the majority of patients. However, the overall response rates in other malignancies such as chronic lymphocytic leukemia are around 50%. This could be partially related to CART exhaustion and dysfunction induced by leukemia cells. In this study, we aim to evaluate the role of inhibitory receptors/pathways in inducing CART cell dysfunction and exhaustion in hematological malignancies. As a tumor model, we used an acute myeloid leukemia (AML) cell line (MOLM14) and primary AML samples and treated them with CD33 or CD123 directed CART cells (second generation CARs using 4-1BB and CD3z signaling domains and a lentiviral vector). Incubation of primary AML samples or MOLM14 cell line with CD33 or CD123 directed CARTs resulted in a significant up-regulation of PD-L1 on tumor cells after 24 hours of incubation (0% on day 0 vs 80% on day 1, P <0.001), and up-regulation of PD-1 and TIM-3 on T cells 3-7 days post co-culture (8% of T cells expressed PD-1 on day 0 vs 43% on day 3, P=0.03 and 13% of T cells expressed TIM-3 on day 0 vs 71% on day 3, p=0.001, Figure 1). For in vivo experiments, we used NSG (NOD-SCID-g-/-) mice and engrafted them with the MOLM14 cell line. Treatment of these AML xenografts with suboptimal doses of CD33 or CD123 CARTs resulted in initial anti-tumor responses, followed by disease relapses in 40-60% of the mice (Figure 2A). T cells were isolated from the bone marrow of these mice and analyzed for differential expression of inhibitory receptors. There was a significantly increased up-regulation of TIM-3 receptors on T cells isolated from mice with relapsed disease compared with T cells isolated from mice in remission after CART cell therapy (Figure 2B). Next, we investigated the role of adding checkpoint blockade to improve T cell function ex vivo after CART cell therapy. Marrows of mice that relapsed after CART cell therapy contained both residual CART cells and leukemia and were used to model the administration of checkpoint blockade in the setting of CART cell exhaustion. Cells were cultured with PD-1 or TIM-3 blocking antibodies or the combination of both (10 ug/ml for 72 hours). CART cell effector functions such as cytokine production and Ki-67 proliferation marker improved in the presence of checkpoint antagonists especially when both PD-1 and TIM-3 blocking antibodies were combined (figure 2C). Finally, we tested the combination of checkpoint blockade with CARTs in AML xenografts. In this approach, we treated MOLM14 xenografts with suboptimal doses of CD33 or CD123 directed CARTs or with control untransduced T cells (UTD), with or without checkpoint blocking antibodies. NSG mice bearing MOLM14 AML xenografts were established. Engraftment was confirmed by bioluminescent imaging. The tumor bearing mice were then treated with suboptimal doses (0.25-0.5 x106 total T cells I.V) of CD33 or CD123 directed CARTs or with control untransduced T cells (UTD). Mice also received PD-1 blockade, TIM-3 blockade or the combination of both on days 3, 6, 9 and 12 post T cell therapy, with the rationale for early checkpoint blockade being based on our in vitro observations of early upregulation of inhibitory ligands on AML after exposure to CART cells. Mice were then followed with serial imaging to assess disease burden. The addition of checkpoint antagonists to untransduced T cells, in particular anti-TIM3, did not lead to an anti-leukemic effect. However, the addition of PD-1 or TIM-3 blockade to CART cell therapy resulted in a synergistic anti-tumor activity as shown in Figure 3. The durable complete response rate was: 45% for treatment with CART123 alone, 80% for treatment with CART123+PD-1 blockade, 100% for treatment with CART123+TIM-3 blockade, and 80% for treatment with CART123+ both PD-1 and TIM-3 blockade). Our preclinical results indicate that PD-1 and TIM-3 pathways are involved in CART exhaustion and dysfunction in AML. Combination of checkpoint inhibitors with CART cells may lead to enhanced efficacy in AML and other hematological malignancies. Current studies are investigating mechanisms of synergy and the role of these combinations in other hematological malignancies. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Kenderian: Novartis: Patents & Royalties, Research Funding. Ruella:Novartis: Patents & Royalties, Research Funding. Porter:Novartis: Patents & Royalties, Research Funding. June:University of Pennsylvania: Patents & Royalties: financial interests due to intellectual property and patents in the field of cell and gene therapy. Conflicts of interest are managed in accordance with University of Pennsylvania policy and oversight; Novartis: Research Funding. Gill:Novartis: Patents & Royalties, Research Funding.

Abstract Relapsing/refractory (r/r) B-cell Acute Lymphoblastic Leukemia (ALL) is associated with a poor prognosis in both pediatric and adult patients. Novel therapies targeting CD19 on leukemic blasts, such as anti-CD19 Chimeric Antigen Receptor T cells (CART19, CTL019) or bi-specific anti-CD19/CD3 antibodies (blinatumomab) induce significant responses in this population. However, CD19-negative relapses have been reported in 5-10% of patients following CART19 or blinatumomab therapies. This is likely due to selective pressure on leukemia sub-clones by these potent anti-CD19 agents. Hence, novel effective immunotherapies are needed in order to treat these patients. In order to identify potential additional B-ALL antigens, samples from 20 r/r patients (including two that relapsed with CD19-negative disease after treatment with CART19 therapy) were screened using a custom Quantigene RNA panel (Affymetrix) and expression on cell surface was confirmed by multiparametric flow cytometry. The IL-3 receptor α (CD123) was one of the most highly and homogeneously expressed antigens in the blasts of 16/20 r/r ALL patients, and 2/2 CD19-negative relapses. Therefore, we sought to investigate the role of CART targeting CD123 (CART123) against r/r B-ALL, focusing on treating patients with CD19-negative relapses after prior anti-CD19 directed therapy. CART123 was shown to be effective in eradicating acute myeloid leukemia in xenograft mouse models but its role in ALL has not been investigated (Gill et al, Blood, 2014). We used a 2nd generation CAR123 construct that comprised a 4-1BB (CD137) co-stimulatory domain. T cells were lentivirally transduced and expanded using anti-CD3/CD28 beads. Head-to-head in vitro comparisons between CART123 and CART19 revealed similar rates of proliferation, CD107a degranulation, cytokine production and cytotoxicity when CART were co-cultured with the CD19+CD123+ B-ALL cell line NALM-6 and with primary B-ALL blasts. For in vivo evaluation, we utilized the primary ALL model that was developed by our group (Barrett et al, Blood, 2011). In this model, primary blasts obtained from ALL patients were passaged in NOD-SCID-γ chain KO (NSG) mice, and transduced with GFP/luciferase. We injected NSG mice with 2 million primary ALL blasts i.v. (CD19+, CD123+) and after engraftment, mice were treated with CART19, CART123 or control untransduced T cells (1 million i.v.). Mice treated with control T cells succumbed quickly to disease, while mice treated with either CART19 or CART123 showed tumor eradication and long term survival (Figure 1). We then evaluated the role of CART123 in the treatment of leukemia obtained from an ALL patient that relapsed with CD19-negative disease after CART19 treatment. Both CART123 and CART19 were incubated with CD19-negative ALL blasts; CART123, but not CART19 resulted in significant degranulation, robust cytokine production, and potent cytotoxicity. To confirm these results in vivo, we established a unique model of CD19-negative B-ALL xenograft. We used primary CD19-negative blasts obtained from a pediatric patient that relapsed after CART19 therapy; CD19-negative blasts were passaged in vivo in NSG mice and stably transduced with GFP/luciferase. Importantly, the blasts retained their CD19-negative phenotype. After engraftment, mice were treated with CART19, CART123 or control T cells. CART19 and control T cells had no anti-tumor activity, while CART123 resulted in a complete eradication of the disease and long term survival in these mice (Figure 2). In conclusion, CART123 represents an important additional approach to treating B-ALL, in particular due to its activity against CD19-negative relapses. Since we have previously shown that treatment with CART123 can lead to myelosuppression, CART123 should be employed to eradicate disease prior to allogeneic transplantation. Future direction may include combining CART123 with CART19 preemptively in order to avoid CD19 antigen escapes. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Ruella: Novartis: Research Funding. Kenderian:Novartis: Research Funding. Shestova:Novartis: Research Funding. Scholler:Novartis: Research Funding. Lacey:Novartis: Research Funding. Melenhorst:Novartis: Research Funding. Nazimuddin:Novartis: Research Funding. Kalos:Novartis: CTL019 Patents & Royalties, Research Funding. Porter:Novartis: Research Funding. June:Novartis: Patents & Royalties, Research Funding. Grupp:Novartis: Consultancy, Research Funding. Gill:Novartis: Research Funding.

Abstract Background: Chronic GVHD contributes to morbidity and mortality after allogeneic transplantation. Several phase 2 and 3 open label studies suggested that ATLG (formerly referred to as ATG-F) reduces cGVHD without impacting relapse or survival. This report describes the first prospective randomized double blind phase 3 trial to assess the effect of ATLG (Neovii) when added to tacrolimus / methotrexate prophylaxis on cGVHD free survival. Patients and Methods: This study was conducted at 27 sites in the United States and Australia. 260 patients were randomized (132 placebo, 128 ATLG). 6 patients who were randomized never received ATLG/placebo (4 placebo and 2 ATLG). Data presented include the 128 placebo and 126 ATLG patients who underwent treatment and transplant. Patients were ages 18-65 years with a diagnosis of acute myeloid (AML, 64%) or lymphoblastic (ALL, 21%) leukemia in first or subsequent complete remission or myelodysplastic syndrome (MDS, 15%) with less than 10% marrow blasts. Median age was 48 years (18-65) with 55% males. All patients received 8/8 HLA (A, B, C, DR) allele matched unrelated products (80% mobilized peripheral blood, 20% bone marrow). Myeloablative conditioning was with cyclophosphamide and total body irradiation (Cy/TBI, 27%), busulfan and cyclophosphamide (Bu/Cy, 33%), or busulfan and fludarabine (Bu/Flu, 40%). All patients received tacrolimus starting on Day -1 and standard mtx on days 1, 3, 6, and 11 for GVHD prophylaxis. Patients received ATLG or placebo on Days -3, -2, -1 at an ATLG dose of 20 mg/kg per day (60 mg/kg total). The primary endpoint of the study was moderate/severe chronic GVHD free survival. cGVHD was scored by the investigator and then confirmed or overturned by an independent adjudication committee. Secondary endpoints included engraftment, acute GVHD , moderate/severe cGVHD, non-relapse mortality, GVHD and relapse free survival (GRFS), progression free (PFS) and overall survival (OS). The impact of ATLG on immune reconstitution was assessed in 91 patients. Results: Treatment arms were balanced with respect to age, diagnosis, remission status, cytogenetics, graft source (PB or BM), CMV serostatus and conditioning regimen. Median follow up of survivors was 745 days (61, 1425). Regarding the primary endpoint, there was no difference in 2 year moderate/severe cGVHD free survival between ATLG and placebo (48 vs 44%, p = 0.57), nor was there a difference in GRFS (Table 1). Neutrophil engraftment at Day 30 was less in the ATLG arm (85% vs 95%, p=0.00001). Grade 2 or higher infusion reactions were higher in the ATLG arm (16% vs 2.3%, p=0.0001). Reactivation of CMV was similar (27% vs 31%, p=0.58). The Day 180 cumulative incidence of grades 2-4 acute GVHD was lower in the ATLG arm (23 vs 40%, p = 0.003) as was the 2-year cumulative incidence of moderate/severe cGVHD (12 vs 33%, p = 0.000006). However, both 2-year OS and PFS were lower in ATLG treated patients (58 v 76% and 47 vs 67%, respectively) due in part to a higher incidence of relapse (32 vs 19%, p=0.068). Multivariable models confirmed that ATLG was associated with inferior OS, HR 1.85 (1.1-2.9, p=.0075) and PFS, HR 1.63 (1.1-2.41, p=0.015). We then conducted an unplanned post-hoc analysis and discovered a striking influence of conditioning regimen on outcomes. There were no differences in OS or PFS between ATLG and placebo arms in patients receiving Bu/Cy or Bu/Flu but a dramatic difference in patients receiving Cy/TBI conditioning (OS, 88% vs 48% p =0.006 and PFS, 75 vs 29%, p=0.007 in placebo and ATLG arms, respectively). 91 patients (44 ATLG, 47 placebo) participated in the immune reconstitution study. ATLG treatment was associated with lower CD3, CD4, and CD8 counts at Days 30, 100, and 360, respectively. In turn lower CD3, CD4, and CD8 counts assessed as time dependent variables were all associated with inferior OS and PFS as well as higher NRM (data not shown). Conclusion: In this first ever prospective, randomized, double blind trial of ATLG added to tacrolimus /methotrexate in recipients of matched unrelated donor grafts after myeloablative conditioning, there was no significant difference in 2 year moderate/severe cGVHD free survival or GRFS. ATLG did significantly reduce grades 2-4 acute and moderate/severe chronic GVHD. However, overall survival was higher in the placebo arm, driven mainly by patients who received Cy/TBI conditioning. Further analyses are needed to understand the proper role for ATLG in HCT. Disclosures Soiffer: Juno: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Porter:Genentech: Employment; Novartis: Patents & Royalties, Research Funding. Jagasia:Therakos: Consultancy. Szer:Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ritz:Kiadis: Membership on an entity's Board of Directors or advisory committees. Glavin:Neovii Biotech: Employment. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

Abstract Clinical GVHD staging varies between centers and is not agreed upon by independent reviewers (Weisdorf, BBMT 2003). These inconsistencies help explain why promising GVHD treatments from single center studies have not reproduced in multicenter trials. To address this issue, our international GVHD research consortium has developed guidance that has been refined through consensus following case discussions, resulting in uniform and reproducible GVHD clinical symptom reporting. We record all raw target organ symptom data and apply staging based upon this data (Table 1). Only areas of erythema, bullae and desquamation are quantified because other skin changes are not typical of active GVHD rash. Upper GI symptoms must meet thresholds to diagnose GVHD: anorexia with associated weight loss, nausea and/or 2+ vomiting episodes/day lasting 3+ days. For lower GI GVHD we collect stool volumes excluding formed/mostly-formed stools. Unquantified episodes are counted at 200 ml per episode (3 ml/kg for children <50kg) based upon a chart review of 300 patients with post-BMT diarrhea from any cause. Non-GVHD rectal bleeding that results in flecks or streaks of blood in the stool are ignored for staging. We use the highest daily stool output in the 3 days prior to the diagnosis of lower GI GVHD to determine onset stage and, when available, a 3-day average stool volume for subsequent staging to smooth daily variability. We classify biopsy report interpretation into four standardized categories: Positive (unequivocal presence of GVHD), Equivocal (findings suggestive of GVHD, but the pathologist cannot confirm the diagnosis), Non-diagnostic (no abnormalities or subtle findings insufficient to determine etiology), and Non-GVHD etiology (definitive evidence of another diagnosis without concomitant features suggestive of GVHD). We then combine the biopsy interpretation with clinical decision making to assign an overall confidence level to the diagnosis of GVHD in each target organ (Table 2): Confirmed (positive biopsy, regardless of clinician treatment decision), Probable (GVHD diagnosis is sufficiently favored that treatment is given without a positive biopsy), Possible (symptoms present without a positive biopsy; not treated as GVHD), Negative (no symptoms or symptoms are present but a GVHD diagnosis is not entertained and a non-GVHD etiology is identified). Uniform clinical data collection is essential for future GVHD trials and requires application of clear guidance. While still subject to refinement, these guidelines, in use for 2 years by an international research consortium, are designed to be clear, easy to apply, and for clinical trial use. Table 1. GVHD Target Organ Staging Stage Skin (active erythema only) Liver (bilirubin) Upper GI Lower GI (stool output/day) 0 No active (erythematous) GVHD rash < 2 mg/dl No or intermittent nausea, vomiting or anorexia Adult: < 500 ml/day or <3 episodes/day Child: < 10 ml/kg/day or <4 episodes/day 1 Rash < 25% BSA 2-3 mg/dl Persistent nausea, vomiting or anorexia Adult: 500-999 ml/day or 3-4 episodes/day Child: 10 -19.9 ml/kg/day or 4-6 episodes/day 2 Rash 25 - 50% BSA 3.1-6 mg/dl - Adult: 1000-1500 ml/day or 5-7 episodes/day Child: 20 - 30 ml/kg/day or 7-10 episodes/day 3 Rash > 50% BSA 6.1-15 mg/dl - Adult: >1500 ml/day or >7 episodes/day Child: > 30 ml/kg/day or >10 episodes/day 4 Generalized rash (>50% BSA) and bullous formation or desquamation > 5% BSA >15 mg/dl - Severe abdominal pain with or without ileus, or grossly bloody stool (volume independent) Table 2. Confidence Levels Pathologic evidence Clinician assessment Treatment for acute GVHD Comments Confirmed Unequivocal evidence of GVHD GVHD is the etiology for symptoms Not required GVHD is clearly present even if other etiologies co-exist simultaneously Probable Not required (includes equivocal and non-diagnostic biopsies) GVHD most likely etiology for symptoms Yes GVHD is most likely present but other etiologies may also explain the symptoms and there insufficient evidence to make a confirmed diagnosis Possible GVHD in differential diagnosis (but no treatment is being provided) No GVHD may be present, but other etiologies are favored Negative Unequivocal evidence of a diagnosis other than GVHD (e.g., drug rash) GVHD is not considered as an explanation for the symptoms No and the symptoms resolve without GVHD treatment A "negative" biopsy (e.g., normal skin) is not unequivocal evidence of a diagnosis other than GVHD Disclosures Devine: Genzyme: Research Funding. Chen:Bayer: Consultancy, Research Funding. Porter:Novartis: Patents & Royalties, Research Funding. Levine:Novartis: Consultancy.

Abstract Abstract 739 The combination of a calcineurin inhibitor and methotrexate has been the standard of care in graft-vs.-host disease (GVHD) prophylaxis for over 25 years, with resultant rates of grade II-IV acute GVHD between 30–50%. The mTOR inhibitor, sirolimus, has demonstrated promise in a number of Phase II trials as an immunosuppressant used for GVHD prophylaxis. The BMT CTN, sponsored by the NHLBI and NCI, conducted a multicenter, randomized controlled trial comparing the combination of tacrolimus and sirolimus (Tac/Sir) with tacrolimus and methotrexate (Tac/Mtx) as GVHD prophylaxis after matched, related donor (MRD) hematopoietic stem cell transplantation (HSCT). Methods: Eligible patients were between ages 2 – 60 years, and had acute leukemia in remission, myelodysplasia or chronic myeloid leukemia in chronic or accelerated phase. All had adequate organ function, and a 6/6 HLA-A, B, DRB1 matched sibling donor. 304 patients were randomly assigned to either Tac/Sir (n = 151) or Tac/Mtx (n = 153) as GVHD prophylaxis after TBI-based conditioning and MRD HSCT. An intent-to-treat analysis was performed on the primary endpoint of Grade II-IV GVHD-free survival 114 days from randomization. Ten subjects who received busulfan-based conditioning and were previously reported were excluded from analysis. Three subjects who did not undergo HSCT are included in the primary analysis, but not secondary analyses. Results: Treatment groups were well balanced. The median age of participants was 44 years (range 13 – 59) and 83% had acute leukemia. Neutrophil and platelet engraftment were both faster in the Tac/Sir group (14 vs. 16 days, p < 0.001; 16 vs. 19 days, p = 0.03, respectively), but this did not affect the time to first hospital discharge (20 vs. 21 days, p = 0.37). The incidence of grade II-IV and grade III-IV acute GVHD at 100 days were lower in the Tac/Sir group (26 vs. 34%, p = 0.17; 8 vs. 15%, p = 0.05). Day 100 treatment-related mortality was no different between groups (7 vs. 7%, p = 0.43). The primary endpoint of 114-day acute GVHD-free survival was not statistically different between groups (67 vs. 62%, p = 0.38, Figure). The cumulative incidence of relapse at 2 years from transplantation was not different between groups (27 vs. 30%, p = 0.81). The competing-risk cumulative incidence of chronic GVHD was higher in the Tac/Sir arm (54 vs. 43%, p =0.044). Overall toxicities were not different between groups, with two notable exceptions. The peak and average OMAS oral mucositis scores were lower in the Tac/Sir arm (peak 0.70 vs. 0.96, p < 0.001; average 0.31 vs. 0.47, p < 0.001), however, there was an increased rate of the endothelial injury syndromes, veno-occlusive disease (11 vs. 4%, p = 0.03), and thrombotic microangiopathy (5 vs. 1%, p = 0.05) in the Tac/Sir arm. Causes of death were not different between groups. At 2 years from transplantation, disease-free (DFS) and overall survival (OS) were not different between study arms (DFS 53 vs. 53%, p = 0.76; OS 60 vs. 61%, p = 0.44). Conclusions: No difference in 114-day acute GVHD-free survival was noted between treatment arms. Compared with Tac/Mtx in MRD HSCT, Tac/Sir is associated with more rapid engraftment, less severe acute GVHD and oral mucositis, excess chronic GVHD and endothelial injury syndromes, and similar long-term outcomes. Understanding the trade-offs between regimens, Tac/Sir can be used as an alternative to Tac/Mtx in MRD HSCT. Disclosures: Cutler: Pfizer, inc: Research Funding; Astellas, Inc: Consultancy, Research Funding. Off Label Use: Sirolimus - Prevention of GVHD Tacrolimus - Prevention of GVHD. Waller:Outsuka: Research Funding.