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Background Post-transplant cyclophosphamide (PTCY) is being increasingly used for graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT) across various donor types. However, immune reconstitution after PTCY-based vs. conventional GVHD prophylaxis has not been well studied. Methods We evaluated the pace of immune reconstitution (CD4+ T-cell, CD8+ T-cell, NK-cell and B-cell) at 3 months, 6 months and 1 year post-HCT in 583 adult patients receiving myeloablative (n=223) or reduced intensity conditioning (n=360) HCT (2012-2018). Haploidentical (Haplo; n=75) and 8/8 HLA-matched unrelated (MUD, n=508) donor types were included. GVHD prophylaxis was PTCY-based in 75 Haplo and 38 MUD (MUD-PTCY) HCT, while tacrolimus/methotrexate (TAC/MTX) was used in 89 and TAC/Sirolimus (TAC/SIR) in 381 MUD HCT. Clinical outcomes including viral infections, non-relapse mortality (NRM) and overall survival (OS) were compared across all four treatment groups. Results The recovery of absolute total CD4+ T-cell count after Haplo-PTCY and MUD-PTCY was significantly lower compared to MUD TAC/MTX or MUD TAC/SIR throughout 1 year of HCT (Figure). In contrast, CD19+ B-cell recovery at 6 months and thereafter was more rapid after Haplo-PTCY and MUD-PTCY HCT in comparison to MUD TAC/MTX and MUD TAC/SIR. In subgroup analysis compared to MUD TAC/MTX HCT, total CD8+ T-cell or NK-cell recovery was not significantly different after Haplo-PTCY or MUD-PTCY HCT. However, patients receiving MUD TAC/SIR vs. MUD TAC/MTX had significantly slower reconstitution of total CD8+ T-cells up to 6 months and CD19+ B-cells at 1 year of HCT, but no significant differences in CD4+ T-cell or NK-cell recovery. The distribution of recipient CMV serostatus was similar in all four groups: 72% in Haplo-PTCY, 62 % in MUD-PTCY HCT, 68% in MUD TAC/MTX and 63% in MUD TAC/SIR (p=0.11). Cumulative incidence of CMV reactivation/infection at 1-year of HCT was higher in patients receiving Haplo-PTCY (39.6%) or MUD TAC-MTX (37.7%) compared to those receiving MUD-PTCY (27.0%) or MUD TAC/SIR (22.8%; p Conclusion Our data demonstrate that the pattern of immune reconstitution after HCT is different after PTCY-based vs. conventional GVHD prophylaxis with delayed total CD4+ T-cell but more rapid B-cell recovery after PTCY-based GVHD prophylaxis. The rates of CMV and EBV viral infections were different across the donor types. However, these differences had no significant influence on NRM or survival after HCT.

Introduction Immune suppressive donor regulatory T cells (Tregs) can be expanded to prevent or treat graft-versus-host disease (GVHD). In human induced Tregs (iTregs), we demonstrated that inhibiting STAT3 phosphorylation (pSTAT3) with S3I-201 increases demethylated Foxp3 and significantly improves their suppressive potency in vitro, mitigating phenotypically plastic iTreg de-differentiation. Objectives To investigate whether human pSTAT3-inhibited iTregs 1) prevent GVHD and 2) maintain donor immunity against leukemia. Methods Our human skin/NSG mouse xenograft model is relevant to GVHD and permits preclinical testing of human pSTAT3-inhibited iTregs in vivo. NSG mice were transplanted with a 1cm2 human skin graft, followed by 5 × 106 allogeneic peripheral blood mononuclear cells with or without 1 × 105 iTregs, dendritic cell-expanded for 5 days with S3I-201 or DMSO. Results We now show human pSTAT3-inhibited iTregs prevent skin graft rejection by alloreactive T cells and spare the anti-leukemia activity of donor cytotoxic T lymphocytes (CTL) (Figure 1A-C). Compared to DMSO-treated iTregs, pSTAT3-inhibited iTregs upregulate skin-homing CLA, as well as immune suppressive IL-9, GARP, and PD-1 (P Conclusion We demonstrate that human pSTAT3-inhibited iTregs can prevent GVHD-mediated tissue damage, preserve anti-leukemia CTL function, and that metabolic reprogramming with coQ10 significantly enhances their suppressive potency. Based upon these data, we will clinically test the safety and efficacy of human pSTAT3-inhibited iTregs in GVHD prevention.

Introduction Mycophenolate mofetil (MMF) dose/kg can influence clinical outcomes of allogeneic hematopoietic cell transplantation (HCT) including acute graft-versus-host disease (GVHD) (Harnicar BBMT 2015; Bejanyan BBMT 2018). When used for GVHD prophylaxis in conjunction with post-transplant cyclophosphamide (PTCy), MMF is generally dosed at 15 mg/kg three times daily (capped at a maximum of 3 g/day) and combined with either tacrolimus or sirolimus. Thus, many adults receive the maximum dose and a variable dose/kg of MMF. Objectives We sought to investigate the impact of MMF dose/kg on clinical outcomes of HCT in the setting of PTCy-based GVHD prophylaxis, where the effect of MMF dose/kg is unknown. Methods Included are 112 consecutive adult patients with hematologic malignancies who received myeloablative (n=70) or reduced intensity (n=42) HCT at the Moffitt Cancer Center between 2012-2018 with T-cell replete peripheral blood stem cells (n=94) or bone marrow (n=18). GVHD prophylaxis consisted of PTCy/MMF and either tacrolimus (n=57) or sirolimus (n=55). MMF dose relative to patient actual body weight (mg/kg/day), was stratified by tertiles into low ( 40 mg/kg/day, n=36). Results The median age at transplant was 57.8 (range: 21-75) years. Median follow-up was 12 months (range: 0.3-39). Donors were haploidentical related (n=74), mismatched unrelated (n=26), and matched related/unrelated (n=12). MMF dose groups had similar characteristics, except the low dose group having a higher proportion of males (p Conclusion In patients receiving PTCy based GVHD prophylaxis, MMF dose/kg had no significant effect on GVHD. However, lower MMF dose/kg was associated with worse DFS. This study suggests that

European LeukemiaNet (ELN) 2017 updated prognostic system for acute myeloid leukemia (AML), which incorporates both cytogenetic and molecular risks, stratifying patients into 3 distinct genetic risk groups: favorable, intermediate and adverse. While most patients in favorable risk group can be cured with chemotherapy alone, the majority of patients in intermediate and adverse genetic risk groups are considered for curative allogeneic hematopoietic stem cell transplantation (alloHCT). However, the impact of ELN 2017 risk classification on survival of AML patients after alloHCT remains unclear. We examined the prognostic significance of ELN 2017 classification on 503 AML patients in first or second complete remission (373 CR1/ 130 CR2) receiving alloHCT at Moffitt Cancer Center) from 2005-2016. Patients were classified into favorable (n=58, 11.6%), intermediate (n=284, 56.8%) and adverse (n=158, 31.6%) ELN risk groups. The median age at alloHCT for the entire cohort was 55 years (range, 18-76 years) and 29% of all patients had many comorbidities (HCT ≥3) at transplant. Disease risk index (DRI) was low in 38 (7.6%), intermediate in 393 (78.6%) and high in 69 (13.8%) patients, and 22% (n=109) of all patients had secondary AML. Myeloablative conditioning was used in 77% (n=389) of patients, while 23% (n=114) received reduced-intensity conditioning regimen. HLA-matched unrelated donor (47%) was the most commonly used donor type, followed by matched related (27.7%) and mismatched donors (n=75, 9.8%). For the entire cohort, 2-year overall survival (OS) was 56% (52-60%) and leukemia-free survival (LFS) was 51% (47-55%). Patients with CR1 and CR2 status at alloHCT had similar OS (58% vs. 53%, p=0.17). We identified that ELN 2017 genetic risk is prognostic of OS after alloHCT in patients with AML: 72% (61-84%) in favorable risk vs. 60% (54-66%) in intermediate risk vs. 45% (38-53%) in adverse risk groups (p Our findings highlight the prognostic impact of ELN 2017 genetic risk on survival of AML patients undergoing alloHCT in CR1/CR2. Patients in the adverse risk group had higher risk of relapse and worse survival. Thus, ELN 2017 prognostic system can help identify AML patients in CR1/CR2 who can benefit from clinical trials offering relapse reduction strategies in order to improve their survival.

Practice variation in transplant physician management of immune suppression (IS) after allogeneic hematopoietic cell transplantation (HCT) is anticipated to have important consequences, but has not been characterized to date. We conducted a national survey of transplant physician members of the American Society for Blood and Marrow Transplantation to discern variation in IS management, characterize the burden of graft-versus-host disease (GVHD) emerging in the setting of IS taper, and describe the proportion of HCT recipients who successfully discontinue IS by 2 and 5 years post-HCT. There was marked heterogeneity in IS discontinuation practice, with variation in initiation of taper, sequence of agents tapered, frequency of changes, and strategy utilized. Twenty-five percent reported no consistent strategy in their usual practice. Confidence in therapeutic decision making was limited. The majority indicated that they could not predict who would develop GVHD on taper of IS, and reported a resultant burden of both acute and chronic GVHD (aGVHD, cGVHD) emerging or recurring in the setting of IS taper. HCT physicians projected rates of IS discontinuation that increased from 2 to 5 years post-HCT, and differed significantly according to donor relation and stem cell source utilized. The marked variation in practice, burden of GVHD emerging in the setting of IS taper, and limited confidence in therapeutic decision making all highlight shortcomings in an essential component of HCT physicians' scope of practice. These data argue for more rigorous study of IS management post-HCT so that evidence-based practice guidelines can be developed.

Disordered glucose metabolism is a common complication of glucocorticoid therapy for acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT). We aimed to examine the impact of dysglycemia on outcomes in 173 recipients of HCT treated with glucocorticoids for aGVHD. A total of 147 of these patients contributed data to a landmark analysis performed at 12 weeks post-HCT. Median aGVHD onset was 21 days (range: 5–79) after transplant. Median duration of glucocorticoid therapy was 381 days (range: 15–1632). Glucose values were obtained from glucocorticoid initiation date to death or last follow-up, resulting in 11,588 total values. The median (range) for each parameter were: maximum 292 mg/dL (128–694), minimum 75 mg/dL (34–142), average 142 mg/dL (86–327), and standard deviation 46 mg/dL (12–108). Baseline diabetes mellitus predicted significantly greater maximum, mean, and standard deviation. With median follow-up of 20 months (range: 3–55), median overall survival (OS) was 33.7 months (95% confidence interval [CI] 16.4—not reached). On multivariable analysis, maximum, average, or standard deviation of glucose values predicted OS and maximum or average glucose values predicted nonrelapse mortality (NRM). Minimum glucose values of (0–60 mg/dL) were associated with worsened OS and increased NRM. Those patients treated with insulin or oral agents suffered significantly worse OS and increased NRM compared to patients who did not need therapy. Finally, those with sustained maximum values >200 mg/dL despite treatment suffered worse OS and increased NRM. These data suggest an independent adverse effect of dysglycemia in patients treated with glucocorticoids for aGVHD, and argue for stringent glycemic control in this setting.

Glucocorticoids have gone unchallenged as an essential component of primary therapy for acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT) despite limited complete response rates and adverse effects from this therapy. The role for alternate immunosuppressive agents as primary aGHVD treatment remains unexamined. In a series of 10 patients at high risk for corticosteroid toxicity or leukemia relapse who developed biopsy-proven grade II-III aGVHD after hematopoietic cell transplantation, we report that primary therapy with sirolimus resulted in durable complete remission of aGVHD in 5 (50%) without requirement for glucocorticoids. Mild chronic GVHD (cGVHD) developed in 4 (40%). Projected overall survival (OS) at 18 months is 79% (95% confidence interval [CI]: 38.1%-94.3%), and projected relapse-free survival (RFS) at 15 months is 70% (95% CI: 32.9%-89.2%). Sirolimus was well tolerated with mild and reversible thrombotic microangiopathy occurring in 2 patients. This experience provides preliminary evidence for the efficacy of sirolimus as a sole primary therapy in the treatment of aGVHD.

s / Biol Blood Marrow Transplant 21 (2015) S322eS354 S344 Teresa Field , Linda Kelley , Mohamed Kharfan-Dabaja , Frederick L. Locke , Asmita Mishra , Michael L. Nieder , Taiga Nishihori , Jose-Leonel Ochoa-Bayona , Lia Elena Perez , Marcie L. Riches , Claudio Anasetti . 1 Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 2 Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL Standard primary therapy for chronic graft vs. host disease (GVHD) is incompletely effective. Based on biologic insights implicating pathogenic B cells, we conducted a phase I-II trial examining the combination of standard ( 1mg/kg/day prednisone) glucocorticoid therapy with ofatumumab, a humanized anti-CD20 monoclonal antibody, for primary chronic GVHD therapy (NCT01680965). We here report the results of the phase I trial. Patients age 18 with NIH Consensus moderate-severe chronic GVHD newly requiring 1mg/kg/day prednisone were treated at three escalating dose levels (300mg, 700mg, and 1,000mg) of IV ofatumumab on day 1 and 14 of initial glucocorticoid therapy. Dose-limiting toxicity (DLT) was defined by the following: grade 4 infusion reactions, related grade 4 constitutional symptoms, related grade 3 organ toxicities, and grade 4 neutropenia lasting >14 days. Secondary endpoints included: adverse events, infectious complications, clinical response to therapy including reduction in prednisone dose, and serial measures of lymphocyte subsets and immunoglobulins. A total of 12 patients (median age 54, range 25-72) were treated (dose level 1: n1⁄43; level 2: n1⁄43; level 3: n1⁄46). At enrollment, overall chronic GVHD was moderate (n1⁄47) or severe (n1⁄45), with diverse organ involvement (skin: n1⁄48; mouth: n1⁄48; eye: n1⁄48; lung: n1⁄44; GI: n1⁄43; liver: n1⁄45; genital: n1⁄42; joint/fascia: n1⁄45), and both overlap (n1⁄47) and classic (n1⁄45) sub-types were represented. KPS was 80% in 11/12, median platelet count was 164 (range 92287), and median bilirubin 0.6 (range 0.2-0.9). Infusion of ofatumumab was well tolerated: Two infusion reactions (grades 2 and 3) occurred, resolved with supportive care, and all patients completed d1 and 14 infusions. No DLT was observed. From the total number of adverse events (n1⁄427), possibly related AE (n1⁄43) included grade 1 fatigue, grade 1 transaminitis, and grade 3 hand/foot cramping. Infectious complications were expected, and there were no cases of hepatitis B reactivation or progressive multifocal leukoencephalopathy (PML). At 3 months after therapy initiation, overall clinical response among evaluable patients was CR (n1⁄41), PR (n1⁄47), or SD (n1⁄41), and responses were sustained at 6 months (including one conversion from PR to CR). Encouraging reduction in prednisone dose was observed at 3 (median 89%, range 57-100%) and 6 months (median 93%, range 71-100%). Therapy produced significant B-lymphopenia (figure). Ofatumumab in combination with prednisone is safe, and phase II examination of efficacy is ongoing.

s / Biol Blood Marrow Transplant 21 (2015) S266eS321 S297 multivariate analysis using the LASSO approach to logistic regression analysis. Results: Of 134 allo-HSCTs, 29 (21.6%) patients experienced CMV viremia. Among these patients, median age was 51 years (range 27-67), with 48 episodes of viremia. Nine (31%) viremic patients developed CMV disease. CMV disease occurred at a median of 124 days post HSCT (range 61-322). Patients with CMV disease had a median of 2 viremic episodes before disease (range 1-4). Disease occurred at a median of 33 days from the start of the last viremic episode, and 75 days from the start of the first episode of viremia. On univariate analysis, factors associated with progression to CMV disease were: steroid-refractory acute GVHD (60 vs. 20%, p1⁄40.028); number of episodes of viremia >1x103 copies/mL (mean 2.4 vs 1.1, p1⁄40.016); longer duration of viremia (mean 38 vs. 22 days, p1⁄40.01); higher peak viral load (mean 4.49x105 vs. 8.31x103 copies/mL, p 1x103 copies/mL, a longer duration of viremia, and to have failed first-line pre-emptive ganciclovir therapy. This study, while limited, suggests that these risk factors may be predictive of CMV disease. Larger, prospective studies are needed to confirm these risk factors, some of which may be amenable to more aggressive anti-viral therapy.

Evaluation of Melphalan 1-Day Versus 2-Day Dosing in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation Sapna Parmar , Ryan Bookout , Jamie Shapiro , Rebecca Tombleson , Janelle Perkins , Jongphil Kim , Melissa Alsina , Taiga Nishihori . 1 Pharmacy, Moffitt Cancer Center, Tampa, FL; 2 Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, Tamps, FL; 3 Pharmacy, H Lee Moffitt Cancer Center, Tampa, FL; 4 BMT, Moffitt Cancer Center, Tampa, FL; 5 Biostatistics, Moffitt Cancer Center, Tampa, FL; Medicine, Moffitt Cancer Center, Tampa, FL; 7 Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, Tampa, FL

Abstract 1333 In a prior retrospective analysis, we reported no adverse effects of pre-transplant 5-azacitidine on subsequent allogeneic hematopoietic cell transplantation (HCT) outcomes. We now report the results of a prospective observational clinical trial with the objective of evaluating HCT outcomes following pre-HCT therapy with 5-azacitidine. Twenty-three patients seen in consultation for HCT and medically eligible for a donor search were enrolled and received 5-azacitidine [75mg/m2 for 7 days every 4 weeks] until a suitable donor was identified. Four did not proceed to transplant for the following reasons: failure to obtain insurance approval due to patient age, failure of the pre-HCT organ evaluation although a donor was identified, CNS hemorrhage in setting of chronic anti-coagulation five days prior to HCT admission and one (62 years) declined HCT as only a HLA-A mismatched donor was available. Nineteen patients received a HCT following a myeloablative targeted busulfan fludarabine regimen. Median age at HCT was 57 years (25 – 67), 18 patients were older than 45 years, 7 older than 60 years. Disease at diagnosis was RCMD (3), RAEB2 (11), RAEB1 (3), CMML1 (1) and AMLM6 (1). IPSS at diagnosis was Int-1 (2), Int2 (9) and high (5), CMML1 (1), AMLM6 (1) and not evaluable (NE) (1). Cytogenetic risk was good (7), intermediate (5) and poor (7). Three patients had therapy related MDS. Patients received a median of 4 (1-6) cycles of 5-azacitidine. Median time from diagnosis (or time of progression and start of therapy in 2 patients) to HCT infusion was 195 days (107 – 350). Response to 5-azacitidine prior to HCT by the International Working Group 2006 criteria included partial response (8), stable disease (9) and 2 progressed. Two received leukemic induction chemotherapy prior to HCT. Disease status prior to HCT was RCMD (8), RAEB2 (2), RAEB1 (6), CMML1 (2) and AMLM6 (1). IPSS score prior to HCT was Low (1) Int-1 (6), Int2 (9) and poor (1) and CMML1 (2). Source of donor cells was peripheral blood siblings (7), matched unrelated donors (10) and mismatch unrelated donors (2). Median follow-up from HCT is 440 days (83-696). There are 3 patients who did not achieve remission (1) or relapsed (2) and 1 of the three remains alive with active disease. There are 3 non-relapse deaths, 2 due to infection and 1 due to GVHD. All deaths occurred between days 180 – 262. At one year OS is 69% (SE 0.12) and DFS is 63% (SE 0.12). In conclusion, pre-HCT 5-azacitidine was well tolerated, provided control of disease as a bridge to HCT and did not impose additional toxicity after allogeneic HCT with a promising 1 year progression-free survival. Controlled trials are needed to determine whether post-transplant relapse and survival are improved by pre-transplant 5-azacitidine. Disclosures: Field: Celgene: Research Funding. Perkins:Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau. Lancet:Celgene: Research Funding. Alsina:Celgene: Research Funding. List:Celgene: Research Funding. Anasetti:Celgene: Research Funding.

Abstract 3499 Intravenous busulfan (IV Bu) dosing in hematopoietic cell transplantation (HCT) conditioning regimens has been based largely on bioequivalence studies done with the oral dosage form. As systemic exposure to Bu has been correlated to both efficacy and toxicity, we used area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to IV Bu when given daily in combination with fludarabine as HCT conditioning. Three AUC levels were planned: 6000, 7500, and 9000 micromole*min/L, in cohorts of 20 patients (pts) each, with an additional 10 pts to be enrolled at the maximally tolerated AUC. To be included, pts had be 16–65 years old and have a hematologic malignancy, an HLA A, B, C, DRB1 8/8 or 7/8 matched related or unrelated donor, Karnofsky performance status 70–100%, and adequate organ function. The initial dose of IV Bu for the first AUC level was 170mg/m2/day on day -6 and day -5 then, on day -4 and day -3 doses were adjusted based on pharmacokinetic modeling after the first dose to achieve an average daily AUC of 6000. First doses for the subsequent cohorts were based on the linear correlation between AUC and dose in the previous cohort: 180mg/m2/day for AUC 7500 and 220mg/m2/day for AUC 9000, with dose adjustment on days -4 and -3 as described. Pharmacokinetic analysis was done after the day -3 dose to verify the accuracy of the dose adjustments. The first 20 pts in the AUC 6000 cohort (DL1) were coenrolled onto a randomized trial of GVHD prophylaxis (tacrolimus and methotrexate vs tacrolimus and mycophenolate mofetil) and were analyzed separately from a second cohort of 20 pts receiving an AUC 6000 (DL1A) and GVHD prophylaxis with tacrolimus and methotrexate. 20 pts were then enrolled onto AUC 7500 (DL2), followed by 3 pts on AUC 9000 (DL3). All DL3 pts had dose limiting toxicity so accrual to that level was stopped. An additional 9 pts have been treated to date on DL2 (5 of these are Disclosures: Perkins: PDL BioPharma: Research Funding. Off Label Use: IV busulfan was used in combination with fludarabine as conditioning prior to allogeneic hematopoietic cell transplantation in patients with a variety of hematologic malignancies. Field:PDL BioPharma: Research Funding.

Abstract 4548 Acute graft vs. host disease (aGVHD) refractory or dependent on glucocorticoid therapy is a major source of mortality following allogeneic hematopoietic cell transplantation (HCT). Comparative studies to evaluate the efficacy of available salvage immune suppressive agents are lacking. We retrospectively compared the efficacy of sirolimus (SIR) and mycophenolate mofetil (MMF) as salvage aGVHD therapy for glucocorticoid refractory, dependent or intolerant patients. Of 281 consecutive patients who received HCT at Moffitt Cancer Center from 07/2004 to 09/2009, we identified 84 patients who received tacrolimus/methotrexate (Tac/MTX) as GVHD prophylaxis, were treated with systemic glucocorticoids as first line therapy for acute GVHD grades 2–4, were refractory (n=72) or dependent (n=12) to glucocorticoids, and received second line GVHD treatment with MMF (n=56) or SIR (n=28). Patient demographics and treatment variables were similar between the two groups except for year of transplant, which was earlier for MMF. Median age of the entire group was 50 (range 17 – 68). Disease diagnoses included AML (n=27), NHL (n=14), MDS (n=12), ALL (n=9), CML (n=7), CLL (n=4), SAA (n=2), MPD (n=5), MM/PCL (n=3), and HL (n=1). Conditioning regimens were busulfan/fludarabine for 71, and other regimens for 13. Except for 1 bone marrow graft in each group, all received peripheral blood stem cells. Graft sources were from HLA-matched siblings (35), or 8/8 HLA-matched unrelated donors (49). Overall grade distribution of aGVHD at time of salvage for MMF vs. SIR was the following: grade 1 (13 vs. 2), grade 2 (31 vs. 16), grade 3 (9 vs. 5) and grade 4 (3 vs. 5). Median steroid dose at the time of salvage was 1 (range 0.17 – 2.28) mg/kg for MMF group and 1 (range 0.12 – 2.0) mg/kg for SIR group. Median time from steroid to salvage was 20 (range 1 – 208) days for MMF and 19 (range 1 – 275) days for SIR (p=0.84). Complete response (CR) rates following initiation of MMF or SIR did not significantly differ at the following time points: 1 week (MMF 30%, SIR 21%), 4 weeks (MMF 44%, SIR 46%), and 6 weeks (MMF 60%, SIR 58%). Overall response rates (ORR) also did not differ significantly: 1 week (MMF 57%, SIR 42%), 4 weeks (MMF 57%, SIR 77%), and 6 weeks (MMF 72%, SIR 75%). Flare or progression of aGVHD while on salvage regimen was noted in 50% (MMF) and 36% (SIR) of patients (p=0.64). Median overall survival from the time of salvage therapy for MMF vs. SIR did not significantly differ, 11.6 (95% CI 7.0 – 28.1) vs. 9.7 (95% CI 5.4 – 15.9) months, log-rank p = 0.88. These retrospective data suggest that MMF and SIR have comparable activity in the treatment of steroid refractory or dependent acute GVHD. Disclosures: No relevant conflicts of interest to declare.

Systemic exposure to high-dose busulfan has been correlated with efficacy and toxicity after hematopoietic cell transplantation for malignancy. We used the area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to i.v. busulfan when given once daily after fludarabine administered at 40 mg/m(2) for 4 days. Three target AUC levels were planned: 6,000, 7,500, and 9,000 μM-min. Included were patients 16 to 65 years old, with a hematologic malignancy, an HLA A, B, or C, DRB1 8/8 or 7/8 matched donor, Karnofsky performance status ≥70%, and adequate organ function. For level 1 patients, i.v. busulfan doses 1 and 2 were 170 mg/m(2)/day, then doses 3 and 4 were adjusted based on first-dose pharmacokinetic modeling to achieve an average daily AUC of 6,000 μM-min. Doses 1 and 2 for the subsequent cohorts were based on the level 1 data: 180 mg/m(2)/day for AUC 7,500 μM-min (level 2) and 220 mg/m(2)/day for AUC 9,000 μM-min (level 3), with pharmacokinetic targeting for doses 3 and 4. Pharmacokinetic analysis after the last dose showed that 88% of the patients had been exposed to a mean AUC within 10% of the target. Forty patients were treated at level 1, 29 patients at level 2, and three patients at level 3. DLT was veno-occlusive disease of the liver, which occurred in none of 40 patients (0%) at level 1, two of 29 patients (7%) at level 2, and three of three patients (100%) at level 3. Dermatitis (P.01) and pulmonary toxicity (P = .01) were also increased at higher AUC levels. Level 2 (7,500 μM-min × 4 days) was the maximally tolerated AUC. Within the confines of the trial's small sample size, there was no suggestion that escalating busulfan AUC from 6,000 to 7,500 μM-min × 4 days increased nonrelapse mortality. Assessment of the higher busulfan AUC on relapse prevention requires trials in patients with a homogeneous risk of relapse.

Standard primary therapy for chronic graft-versus-host disease (GVHD) is incompletely effective. Based on biologic insights implicating pathogenic B cells, we conducted a phase I trial examining the combination of standard (1 mg/kg/day prednisone) glucocorticoid therapy with ofatumumab, a humanized anti-CD20 monoclonal antibody, for primary chronic GVHD therapy. Patients ages ≥ 18 with National Institutes of Health Consensus moderate-to-severe chronic GVHD newly requiring 1 mg/kg/day prednisone were treated at 3 escalating dose levels (300 mg, 700 mg, and 1000 mg) of i.v. ofatumumab on days 1 and 14 of initial glucocorticoid therapy. Dose-limiting toxicity (DLT) was defined by grade 4 infusion reactions, related grade 4 constitutional symptoms, related grade ≥ 3 organ toxicities, or grade 4 neutropenia lasting > 14 days. A total of 12 patients (median age 54; range, 25 to 72) were treated (dose level 1: n = 3; level 2: n = 3; level 3: n = 6). At enrollment, overall chronic GVHD was moderate (n = 7) or severe (n = 5), with diverse organ involvement (skin: n = 8; mouth: n = 8; eye: n = 8; lung: n = 4; gastrointestinal: n = 3; liver: n = 5; genital: n = 2; joint/fascia: n = 5). Infusion of ofatumumab was well tolerated, and no DLT was observed. From the total number of adverse events (n = 29), possibly related adverse events (n = 4) included grade 1 fatigue, grade 1 transaminitis, and 2 infusion reactions (grades 2 and 3). Infectious complications were expected, and there were no cases of hepatitis B reactivation or progressive multifocal leukoencephalopathy. Ofatumumab in combination with prednisone is safe and a phase II examination of efficacy is ongoing.

The selective IMPDH inhibitor, mycophenolate mofetil (MMF), has entered the clinic with the promise to provide potent immune suppression without the side effects of methotrexate (MTX) or other broad-spectrum immunosuppressants. The use of MMF in the prevention of GVHD after hematopoietic cell transplantation (HCT) has been increasing worldwide, but only one small controlled study comparing cyclosporine + MMF to cyclosporine + MTX has been conducted to date. We compared GVHD prophylaxis with tacrolimus + MTX (TAC/MTX) to tacrolimus + MMF (TAC/MMF) in a single institution, randomized, controlled trial. Eligible patients were to receive T-replete peripheral blood HCT from 10/10 or 9/10 HLA-A, B, C, DRB1 and DQB1 matched donors, and have no contraindications to the use of TAC, MTX, or MMF. Randomization was stratified based on conditioning regimen intensity. Ninety-two pts were randomized, 45 to TAC/MMF and 47 to TAC/MTX and were all included in the intent-to-treat (ITT) analysis. Two pts were not transplanted and one pt withdrew consent prior to transplant. These pts were all randomized to TAC/MMF and excluded in the modified ITT (MITT) analysis. Pts received TAC 0.03 mg/kg/24hr as a continuous IV infusion beginning day -3 with doses adjusted to maintain whole blood levels of 5–15ng/ml. Pts were converted to PO therapy as tolerated and tapered after 6 months in the absence of GVHD. MTX was given IV at doses of 15mg/m2 day +1 and 10mg/m2 on days +3, +6 and +11. In pts with renal insufficiency, MTX doses were adjusted per pts’ pretransplant creatinine clearance. MMF was dosed at 15 mg/kg every 12 hours (up to 3g/d) IV beginning day 0, switched to PO as tolerated and continued for 12 months. Acute GVHD was graded weekly by Thomas’ criteria, modified per ASBMT consensus criteria; chronic GVHD was scored monthly based on NIH consensus criteria. The groups were balanced with respect to age, diagnosis, disease risk, recipient/donor CMV status, conditioning regimen, donor type and relation. The incidences of grade 2–4 and 3–4 acute GVHD were 79% and 4% in the TAC/MTX arm and 79% and 17% in the TAC/MMF arm (p=1.0 and 0.08, respectively). The incidence of moderate or severe chronic GVHD was 55% in the TAC/MTX arm and 59% in the TAC/MMF arm (p=0.91). By ITT analysis, the cumulative incidence of non-relapse mortality suggested an early difference in favor of TAC/MTX, but at 2 years it was 28% for TAC/MTX arm compared to 32% for the TAC/MMF arm (p=0.41; MITT p=0.33). The cumulative incidence of relapse was 33% in TAC/MTX arm compared to 18% (ITT; 16% MITT) for the TAC/MMF pts (p=0.06; p=0.04 MITT). Overall survival was similar between groups in both the ITT (p=0.76; 62% TAC/MTX vs. 66% TAC/MMF at 1 year) and MITT analysis (p=0.75; 62% TAC/MTX vs. 66% TAC/MMF at 1 year). We conclude that MMF was no better than MTX in preventing acute or chronic GVHD and may perhaps be less effective in preventing more severe forms of acute GVHD. Given the direction of effect we observed in severe acute GVHD, it is unlikely that a larger trial would show benefit for this endpoint. There was a strong suggestion that relapse of malignancy was more frequent after MTX than MMF, apparently in relation to the drug interference with the graft-vs.-leukemia effect. The beneficial effect of MMF on relapse was offset by the early increase in nonrelapse mortality, so that overall survival was unaffected.