Abstract: Abstract 3003FN2 Objective: Progressive disease (PD) remains the main cause of treatment failure following RIC allo-SCT in HL (Peggs KS et al, BJH 2008: 143; 468). We elected to explore the feasibility of adding gemcitabine (G), a highly active agent in relapsed/refractory HL (Santoro A et al, JCO 2000 :18; 2615), to our standard fludarabine (F) - melphalan (M) RIC in patients with relapsed and refractory HL undergoing allo-SCT, with the ultimate goal to augment cytoreduction and reduce the incidence of PD. Main G-associated non-hematologic toxicities include pulmonary, skin toxicities and mucositis. Patients and Methods: Between 8/07 and 3/11, fifteen consecutive HL patients (Unique Patient Number/UPNs 1–15) underwent an allo-SCT with the G-FM regimen. They had failed multiple conventional treatments (median prior chemotherapy regimens: 4; range 2–9), radiation therapy (6/15) and a prior auto-SCT (7/15). The median age was 33 years (range 20–46). Disease status at SCT was chemosensitive relapse (n=4), untreated relapse (n=1), induction failure chemosensitive (n=2), complete remission undetermined (CRU1 and CRU2) (n=8). The median time to PD after auto-SCT was 10 months (range 3–19). The donor was an HLA-identical sibling (n=10) or matched unrelated donor (MUD; n=5, with UPN 6 having a 9/10 match). The conditioning regimen was G 800 mg/m sq IV x1 at day -7 (two patients, UPN 6 and UPN 7 received G 1000 mg/m sq IV x2, day -5 and day -2 as part of a dose escalation attempt stopped for excess toxicity), F (32 mg/m sq IV x4, day -5 to day -2), M (70 mg/m sq IV x2, day -3 and day -2; total dose 140 mg/m sq). Thymoglobulin (4 mg/kg IV) was added in MUD allografts. Graft-vs-host disease (GVHD) prophylaxis included tacrolimus and mini-dose methotrexate (5 mg/m sq). Results: Myeloid recovery was prompt, with an absolute neutrophil count (ANC) 〉 500/mcL at day +12 (range 11–20). Median platelet recovery at 20K/mcL was at day +14 (range 9–26). Chimerism studies indicate 100% donor-derived engraftment in 13/13 evaluable patients (100%). Day 100/overall transplant-related mortality (TRM) were 2/15 (13%) and 2/15 (13%), respectively. Acute GVHD (grade II-IV) occurred in 8/14 evaluable patients, chronic GVHD in 7/13 evaluable patients (extensive in 7). Pulmonary toxicity was seen in four patients (26%). Grade 4 pulmonary toxicity was seen in UPN 6. Otherwise it was grade 1–2 (n=3). Cutaneous toxicity (skin rash, responsive to steroid therapy) was seen in five patients (33%: grade 3 n=1; grade 1–2 n=4). Mucositis was seen in nine patients (60%). It was grade 3 (n=1); grade 1–2 (n=8). Other organ toxicities were not seemingly markedly different from the ones seen with FM140 only. Three patients expired (graft rejection n=1, in UPN 6; CMV pneumonia n=1; PD n=1). Twelve patients are alive (ten progression-free, eleven in CR/CRU) with a median follow-up of 18 months (range 2–33). Actuarial rates of overall survival (OS) and progression-free survival (PFS) at 24 months are 87% (95% CI: 56–96) and 49% (95% CI: 18–74), respectively (see Figure). While a formal comparison with our historical experience with the FM140 regimen is clearly not possible, OS and PFS (actuarial estimates) at 24 months were 64% (95% CI: 49–76), and 32% (95% CI: 20–45), respectively (Anderlini et al, Haematol 2008; 93 :257). Conclusions: The addition of G to FM140 is feasible. Pulmonary, cutaneous toxicities, as well as mucositis, while clinically significant, were manageable and did not contribute to mortality in the patients treated with only one G dose. While quite encouraging, these data remain preliminary. The G-FM regimen deserves further study in a larger cohort of patients. Disclosures: Off Label Use: Gemcitabine, fludarabine and melphalan as part of conditioning regimen for allogeneic stem cell transplantation.

Abstract: Patients with steroid-refractory acute graft versus host disease (aGVHD) have dismal outcomes. Historically, anti-thymocyte globulin has been used in this setting with prior reports demonstrating that even when patients respond, long-term survival occurs in only 5% of patients (Arai et al, 2012). Unfortunately, no therapy has been shown to improve outcomes for this high-risk group. Pentostatin, a potent adenosine deaminase inhibitor, was previously tested in a phase 1/ 2 study in steroid-refractory aGVHD and demonstrated an overall survival (OS) of 25% with a median follow-up of 〈 3 months (m). We performed a retrospective review of patients receiving pentostatin for steroid-refractory aGVHD with the goal of characterizing long-term outcomes. Methods: All patients transplanted at MD Anderson Cancer Center from January, 2006 to December, 2014 who received at least one dose of pentostatin for steroid-refractory aGVHD were included in this analysis. Pentostatin was dosed at 1.5 mg/m2 on days 1-3 and repeated every two weeks as indicated. Patients who received the drug as GVHD prophylaxis, upfront therapy, beyond third-line, for classic chronic GVHD or following relapse were excluded. Primary endpoints included day 28 response and OS. Results: A total of 60 patients received pentostatin as second (n=22) or third line (n=38) treatment for steroid-refractory aGVHD. The median age was 52 years (range, 2-70). First dose of pentostatin was administered at a median 69 days post-transplant (27-595) with a median of 3 doses provided (range, 1-9). A majority of patients had steroid-refractory lower GI (78%) and/or liver (43%) GVHD. Baseline characteristics described in table 1. The median time from initiation of steroids to pentostatin was 15 days (range, 4-172). OS at 18 m after pentostatin initiation was 21%, with median follow-up of 19 m (range, 7-77).A total of 22 (37%) patients died before day 28 and were considered non-responders. Day 28 response rate was 33% with 20 patients achieving a complete (n=11) or partial response (n=9). Pentostatin administration 〈 10 days following initiation of steroid was the only predictor for day 28 response (HR 2.2, 95% CI 1.2-4.3, p=0.02). The median survival was 25 and 341 days in non-responders and responders, respectively. Landmark analysis starting on day 29 after pentostatin is shown in figure 1. Predictors for OS on multivariate analysis at 18 m included: day 28 complete/partial response (CR/PR) as a time dependent variable (HR 0.3, 95% CI 0.1-0.7, p=0.005), liver GVHD (HR 2.2, 95% CI 1.2-4.1, p=0.007), and age 〉 60 (HR 1.9, 95% CI 0.99-3.6, p=0.05). Within our analysis, patients destined for early mortality within 30 days of pentostatin exhibited all these features: liver GVHD, receipt of pentostatin 〉 100 days from transplant, and age 〉 60, with an OS of 35% at 30 days compared to 72% in the absence of these features (p=0.001). Conclusions: Patients with steroid refractory aGVHD have dismal outcomes. However, long-term survival does occur, especially when additional therapy is administered promptly. Novel strategies to identify patients who are destined to fail upfront therapies are likely to improve outcomes. We identified that earlier dosing of pentostatin after recognition of steroid refractoriness improved response rates. Further, patients without liver GVHD and who were ≤60 had better OS, identifying those who will benefit most from this therapy. Conversely, pentostatin should be avoided in patients 〉 60 with liver GVHD as these patients had extremely high mortality with two-thirds dying by day 30. Table 1. Baseline characteristics at pentostatin initiation. Variable Patients (N=60) Preparative Regimen Intensity  Non-myeloablative (%) 22 (37)  Ablative (%) 38 (63) Overall GVHD Grade  2 (%) 11 (18)  3 (%) 21 (35)  4 (%) 28 (47) Skin GVHD Stage  0 (%) 48 (80)  1 (%) 4 (7)  2 (%) 5 (8)  3 (%) 3 (5) Lower GI GVHD Stage  0 (%) 12 (20)  1 (%) 10 (17)  2 (%) 6 (10)  3 (%) 11 (18)  4 (%) 20 (33)  Unknown (%) 1 (2) Liver GVHD Stage  0 (%) 33 (55)  1 (%) 4 (7)  2 (%) 9 (15)  3 (%) 6 (10)  4 (%) 7 (11)  Unknown (%) 1 (2) Number of GVHD sites  1 (%) 40 (67)  2 (%) 15 (25)  ≥3 (%) 5 (8) Day 28 Response  CR (%) 11 (18)  PR (%) 9 (15)  No Response (%) 11 (18)  GVHD Progression (%) 5 (9)  Died by Day 28 (%) 22 (37)  Progression of Malignancy (%) 2 (3) Figure 1. OS, starting at day 29, stratified by response. Figure 1. OS, starting at day 29, stratified by response. Disclosures Alousi: Therakos, Inc: Research Funding.

Abstract: BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication of allogenic hematopoietic stem cell transplantation (AHSCT), particularly in recipients of alternative donor transplants, which are being performed in increasing numbers. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, without a definitive therapeutic option. METHODS We performed a clinical trial (ClinicalTrials.gov identifier: NCT02479698 ) to assess the feasibility, safety, and efficacy of administering most closely HLA-matched third-party BKV-specific cytotoxic T lymphocytes (CTLs), generated from 26 healthy donors and banked for off-the-shelf use. The cells were infused into 59 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed. RESULTS Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-versus-host disease, graft failure, or infusion-related toxicities. BKV-CTLs were identified in patient blood samples up to 3 months postinfusion and their in vivo expansion predicted for clinical response. A matched-pair analysis revealed that, compared with standard of care, after accounting for prognostic covariate effects, treatment with BKV-CTLs resulted in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement. CONCLUSION Off-the-shelf BKV-CTLs are a safe and effective therapy for the management of patients with BKV-HC after AHSCT.

Abstract: Background: There is a role of novel preparative regimens to further improve the outcome after high-dose chemotherapy and autologous hematopoietic stem cell transplantation (ASCT) in multiple myeloma. Arsenic trioxide (ATO) has synergistic activity with melphalan and ascorbic acid (AA) both in vitro and in vivo, and this 3-drug combination was found to be safe and feasible in both conventional and high-dose settings. Bortezomib, a proteasome inhibitor, is an active agent in newly diagnosed or relapsed multiple myeloma in conventional therapy setting. We conducted a randomized phase II trial to determine the safety and efficacy of a combination of ATO, AA and melphalan with or without bortezomib as preparative regimen in patients with myeloma. Methods: Sixty patients were enrolled and 58 patient received ASCT between October 2006 and September 2007. One patient developed respiratory failure and another developed extensive pulmonary embolism after enrollment and did not proceed to ASCT. All 58 evaluable patients received melphalan 100 mg/m2 IV on days -4 and -3, AA 1000 mg/day IV on days -9 to -3 and ATO 0.25 mg/kg IV on days -9 to -3. Patients were randomized to 3 arms; no bortezomib (arm 1), bortezomib 1 mg/m2 on days -9, -6 and -3 (arm 2), and bortezomib 1.5 mg/m2 on days -9, -6 and -3 (arm 3). Patients were also asked to fill out a standardized Quality of Life (QOL) questionnaire at enrollment and at 6 months post-ASCT. Results: Median age of patients in arms 1, 2 and 3 were 61, 59 and 64 years, respectively (p=0.08). Median interval between diagnosis and ASCT were 12.2, 9.6 and 8.8 months, respectively (p=0.3). Cytogenetic abnormalities were detected in 2, 5 and 8 patients in arms 1, 2 and 3, respectively (p=0.08). With a median follow up of 11.4 months (range 5 to 20) post ASCT in surviving patients, cumulative non-relapse mortality was1.7%. Grade 3–4 toxicity was seen in 6 patients in arm 1 (mucositis 3, dyspnea 1, acute renal failure 1, pleural effusion 1), 6 patients in arm 2 (mucositis 3, diarrhea 1, pneumonia 1 and hydronephrosis 1) and 6 patients in arm 3 (pulmonary edema 2, mucositis 1, intestinal obstruction 1, low back pain 1, elevated transaminases 1) (p=0.9). The most common adverse events were nausea, diarrhea and pedal edema. Grade 1–2 weight gain due to fluid retention was seen in 84, 70 and 95% of patients in arms 1, 2 and 3, respectively (p= 0.1). Median time to neutrophil engraftment (ANC 〉 500/dl) was 10 days in each arm. Complete response rates in arms 1, 2 and 3 were 26, 10 and 16%, respectively (0=0.4). Kaplan-Meiers estimates of progression-free survival (PFS) and overall survival (OS) are shown in Figures 1 and 2. Median PFS and OS have not been reached. There was no significant difference in CR, PFS or OS between the 3 arms (p = 0.4, 0.62 and 0.4, respectively). Relapsed disease at ASCT (p=0.003), 〉 12 months interval between diagnosis and ASCT (p=0.05), and cytogenetic abnormalities at diagnosis (p=0.005) predicted a shorter PFS. On a subset analysis, there was no significant difference in PFS or OS between the 3 arms in patients undergoing ASCT in first remission. Fifty-patients submitted their responses to the QOL questionnaire. More patients at 6-month post ASCT reported better overall health (56% vs.12%, p=0.0001). In contrast, more patients at study enrollment reported moderate to severe pain (44% vs. 27%, p=0.09) and debilitating emotional problems (42% vs. 23%, p=0.07). Conclusions: Adding bortezomib to ATO, AA and high dose melphalan is safe and well tolerated as preparative regimen for ASCT in patients with multiple myeloma. Patients with chromosomal abnormalities were predominantly treated in the bortezomib arms without an adverse impact on PFS or OS. Overall QOL indicators showed improvement at 6-month post ASCT. Longer follow up is needed to assess the efficacy of this combination. FIGURE 1 FIGURE 1. FIGURE 2 FIGURE 2.

Abstract: HLA-matched siblings are better than HLA-matched unrelated donors for patients with good performance scores Survival rates are comparable after HLA-matched sibling and unrelated donor transplantations for patients with poor performance scores

Abstract: Background: Encouraging results have been reported in AML/MDS patients (pts) treated with checkpoint inhibitors (CPIs) in frontline and relapsed AML/MDS, and increasing number of pts exposed to CPIs are receiving SCT. However, a high rate of grade 3-4 acute graft versus host disease (aGvHD), 23%, was reported in lymphoma pts following CPI. We performed a retrospective study of pts with AML/MDS treated with an anti-PD1 and/or anti-CTLA-4 blockade at some point prior to undergoing SCT, with the goal of describing transplant outcomes. Methods: In this analysis, we included 30 AML and 13 MDS pts treated with a PD-1 (nivolumab, n=32) or CTLA-4 (ipilimumab, n=9) based therapies on clinical trials, who subsequently had SCT at our institution. Two patients received both nivolumab and ipilumumab. The primary outcome was aGvHD by day 100 after SCT. Secondary outcomes were progression-free survival (PFS) and disease progression. Outcome analyses were stratified by GvHD prophylaxis. Results: Median (med) age was 57 years (yrs) (range, 35-71) (Table 1). Of the 43 pts, 33 (77%) had achieved a best response of complete remission (CR, n=22) or CR without count recovery (CRi/CRp, n=11) to PD-1 or CTLA-4 based therapies, and 2 received PD-1 therapy as maintenance in CR. Med time to response from CPI based therapy was 49 days (range, 21-161). Twelve pts (28%) had no response or lost response to PD-1 and CTLA-4 based therapies prior to proceeding to SCT but achieved a CR/CRi with subsequent therapies (AraC-based therapies in 5, hypomethylator-based therapies in 5, molecular therapies in 2) allowing them to proceed to SCT. Med time to SCT after CPI treatment was 63 days (range, 7-386) and med CPI treatment cycles was 3 (range, 1-10). Conditioning intensity was myeloablative in 22 (51%) pts. Donors were matched related in 7 (MRD, 16%), matched unrated in 25 (MUD, 58%), haploidentical (haplo) in 8 (19%), and cord blood (CB) in 3 (7%) pts. Hematopoietic stem cell source was peripheral blood stem cells (PBSCs) in 25 (53%) and bone marrow (BM) in 17 (40%) pts. GvHD prophylaxis consisted of post-SCT cyclophosphamide (PTCy), 50 mg/kg on days +3 and +4, tacrolimus± mycophenolate mofetil (MMF) (PTCy)(n=22) or tacrolimus and mini-methotrexate/MMF ± antithymocyte globulin (non-PTCy)(n=21). As expected, all haplos had PTCy. None of the CB recipients had PTCy. For MRD and MUD, GvHD prophylaxis was determined by the treating physician; with 57% and 40% of pts receiving PTCy, respectively. There were no significant differences between PTCy and non-PTCy in age, disease, disease status, MRD vs. MUD, donor age, cytogenetics, conditioning intensity, hematopoietic stem cell source, hematopoietic cell transplantation-specific comorbidity index, and number of CPI doses received, except a longer interval between CPI blockade therapy and SCT in PTCy (Table 2). Med follow-up of was 6 months (range, 1.6-23). The 100-day cumulative incidences of grade 2-4 and grade 3-4, aGvHD were 52% and 13% (Table 2). Pts in PTCy group had a trend to lower 100-day grade 3-4 (5% vs 22%, p=0.2). The interval between CPI and SCT did not impact 100-day aGvHD incidence.However, a higher incidence of grade 3-4 aGVHD was observed in patients treated with 〉 4 treatment of PD-1 or CTLA-4 blockade prior to SCT if not given PTCY as GvHD prophylaxis (43% vs. 12%, p=0.01) Considering the association between donor type, stem cell source and aGvHD, subgroup analysis were performed in MUD pts. In 15 MUD patients with PBSC source, there were no grade 3-4 aGvHD in 6 PTCy patients while 4 of 9 non-PTCy patients had grade 3-4 a GvHD (HR=NE due to absence of events in one group, p=0.05). On the other hand, in 10 MUD patients with BM source, no grade 3-4 aGvHD was observed by day 100, in 4 PTCy and 6 non-PTCy pts. At 6-month post SCT, estimated PFS for all pts was 66% (Table 2). PTCy pts had improved PFS at 6 months (p=0.03) and 1-year (p=0.02) post SCT. The med RFS was 4.6 mo in non-PTCy pts while it was not reached in PTCy pts. Conclusion: SCT after PD-1 or CTLA4 based therapies appears feasible in pts with AML/MDS. Our results indicate 1) a high rate of grade 3-4 aGvHD in MUD recipients with PBSC who did not receive PTCy, and 2) improved PFS with the use of PTCy. The use of post-Cy as GvHD prophylaxis to improve the tolerability of SCT in pts treated with PD-1 or CTLA-4 based therapies pre-transplant deserves further investigation. Disclosures Oran: AROG pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding; ASTEX: Research Funding. Ravandi:Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Xencor: Research Funding; Jazz: Honoraria; Orsenix: Honoraria; Jazz: Honoraria; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Xencor: Research Funding; Seattle Genetics: Research Funding; Orsenix: Honoraria; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria. Kadia:Celgene: Research Funding; Takeda: Consultancy; Takeda: Consultancy; BMS: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy; Novartis: Consultancy; Celgene: Research Funding; Jazz: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Abbvie: Consultancy. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. Konopleva:Stemline Therapeutics: Research Funding. DiNardo:Agios: Consultancy; Abbvie: Honoraria; Celgene: Honoraria; Karyopharm: Honoraria; Medimmune: Honoraria; Bayer: Honoraria. Rezvani:Affirmed GmbH: Research Funding. Shpall:Affirmed GmbH: Research Funding. Champlin:Sanofi: Research Funding; Otsuka: Research Funding. Daver:Pfizer: Research Funding; Incyte: Consultancy; BMS: Research Funding; Novartis: Consultancy; Karyopharm: Consultancy; Daiichi-Sankyo: Research Funding; ImmunoGen: Consultancy; Novartis: Research Funding; Incyte: Research Funding; ARIAD: Research Funding; Karyopharm: Research Funding; Sunesis: Research Funding; Alexion: Consultancy; Kiromic: Research Funding; Otsuka: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy.

Abstract: The use of checkpoint inhibitors (CPI) prior to hematopoietic stem cell transplantation (HSCT) in patients with acute myeloid leukemia and/or myelodysplastic syndromes affects transplantation outcomes, with an especially increased incidence of grade 3 to 4 acute graft‐versus‐host disease (aGVHD). The use of post‐HSCT cyclophosphamide as GVHD prophylaxis in patients treated with CPI prior to transplantation is found to lead to improved transplantation outcomes, including grade 3 to 4 aGVHD.