ALBERT

Description: Outcome of persons 〉65 years with acute myeloid leukemia (AML) is poor. Allogeneic transplant can cure some of these patients but is associated with substantial transplant-related mortality (TRM) and high relapse risk. We analyzed 185 consecutive patients 〉65 years with high-risk AML between 2010 and 2015 who had measurable residual disease (MRD) and molecular risk assessments and who received myeloablative conditioning (MAC, n=42) or reduced-intensity conditioning (RIC, n=143) and a transplant from an HLA-identical sibling (n=66) or a 10/10 loci HLA-matched unrelated donor (MUD, n=119) in order to identify patients who would benefit from allotransplant. MRD was assessed by flow cytometry in bone marrow samples. AML cytogenetic and molecular risk were defined using the 2017 European Leukemia Net genetic risk stratification. The patients who were MRD-negative at time of transplant had a better 2-year cumulative incidence of relapse (CIR 17.6%) and a 2-year overall survival (OS, 69.4%) as compared to the patients in remission but MRD-positive (55.6% CIR, 21.5% OS) or the patients who had morphological evidence of leukemia prior to transplant (48.7% CIR, 19.9% OS), (p

Description: Disease relapse remains the major cause of treatment failure following hematopoietic transplantation for AML/MDS. A major goal is to develop more effective antileukemic regimens without excessive toxicity. Busulfan (Bu)-fludarabine (Flu) is a widely used preparative regimen. We demonstrated that targeting a relatively high busulfan systemic exposure pharmacokinetic (PK) dose adjustment was superior to fixed busulfan dosing. Clofarabine (Clo) has improved antileukemic activity compared to fludarabine. We previously reported a phase I/II study of different dosing combinations of busulfan with Flu and Clo; the best results were obtained with Bu with Flu 10 mg/m2 and Clo 30 mg/m2 daily for four daily doses. We performed a phase III randomized controlled trial to determine if Flu/Clo/Bu improved progression free survival compared to the Flu/Bu regimen. Busulfan was given with PK dose adjustment AUC 6000 mM x min for age

Description: Key Points Ex vivo fucosylation of cord blood cells improves their homing capacities, leading to faster neutrophil and platelet engraftments. This method is quick, safe, and does not require a GMP laboratory; therefore, it can be used widely.

Description: Abstract 2283 Poster Board II-260 Background: Reduced intensity allogeneic transplantation was developed to harness graft versus leukemia immune effect to treat older patients and patients with comorbidities who are not eligible for conventional myeloablative transplant. Aim: To prospectively study the safety and efficacy of reduced intensity HCT in patients with myelofibrosis. Methods: Patients with intermediate or high risk MF were eligible if they had adequate organ function and at least 9/10 matched related or unrelated donor. Fifteen patients were conditioned with Fludarabine 40mg/m2 × 4 (days -5, -4, -3 -2) and Busulfan 130mg/m2 × 2 (day -3,-2). Thymoglobulin 2.5 mg/kg x 3 (day -3,-2 and 1) was additionally given to patients receiving unrelated donor graft. Because of high incidence of relapse, Busulfan dose was increased to a target AUC of 4000 μmol/L or a fixed dose of 100mg/m2 × 4 (days -5, -4, -3 -2) in 11 patients. Tacrolimus and mini Methotrexate were used as graft versus host disease prophylaxis. All patients received standard supportive care. Results: Between 6/2005 and 07/2009, 26 consecutive patients with myelofibrosis were treated. There were 13 males and 13 females with a median age of 58 (range 27-74). Seventeen patients had primary MF, 3 post PV MF and 6 Post ET MF. Based on Lille criteria, 14 patients had intermediate risk disease and 12 had high risk disease. Ten patients had splenectomy prior to transplant; remaining 16 patients had enlarged spleen at the time of transplant. Fourteen patients had mutated Jak 2. Median peripheral blood CD 34 count was 57/μl(range 1-3770/μl). Karyotype was abnormal in 11 patients and diploid in 15. Donors were matched siblings for 10 patients, matched unrelated for 12, and one antigen or allele mismatched unrelated for 4 patients. Stem cell source was marrow in 3 and peripheral blood in 23. All patients engrafted with a median time to neutrophil engraftment of 13 days (0-27) days) and a median time to platelet engraftment of 24 (0-105) days. Jak 2 positive patients achieved molecular remission post transplant with negative JaK 2. With a median follow up of 21 (1-43) months, 2 year overall and event free survival are 71% (SE 10%) and 46% (SE 11%), respectively. Cumulative incidence of non relapse mortality was 14% (SE 7%). Cumulative incidence of relapse was 39% (SE10%). Eight patients relapsed; 3 in blast phase and 5 in chronic phase. Four of these 8 are currently disease free after a second transplant. Including these 4 patients, 18 out of 26 patients are currently disease free. These include 10 of 11 patients treated with higher dose of busulfan compared with 8 of 15 patients treated with lower busulfan dose. Conclusion: RISCT induces molecular remission with very low non relapse mortality in older patients with myelofibrosis, but the relapse rate is high. Increasing the intensity of conditioning regimen may reduce the relapse risk and needs to be studied further. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3415 Poster Board III-303 High dose chemotherapy and SCT is an accepted treatment option for patients with relapsed lymphoid malignancies. Relapse remains a significant issue for patients with advanced disease. Predicting effective disease control with improved safety, we investigated the administration of intravenous (i.v.) busulfan (Bu) combined with melphalan (Mel) in patients with lymphoid malignancies undergoing ASCT. Patients and Methods Bu130 mg/m2 was infused daily for 4 days, either as a fixed dose per BSA (n=20), or to target an average daily AUC of 5,000 uMol-min ± 12% determined by a test dose of i.v. Bu at 32 mg/m2 given 48 hours prior to the high dose regimen (n=82), followed by a rest day, followed by two daily Mel doses at 70mg/m2. Stem cells were infused the following day. Dilantin was given for seizure prophylaxis. Results 102 patients (38 F/64 M) with non-Hodgkin's lymphoma (n=12), Hodgkin's lymphoma (n=49) and multiple myeloma (n=41) with median age 44 years (range 19-66) have been enrolled to date. The median number of prior chemotherapy regimens was 3 (range 1-6). At time of study entry, 88% of patients were in relapse (sensitive relapse n=70, refractory relapse n=19) and 12% were in second remission. The median CD34+ cell dose infused was 5.2 × 106/kg (range 0.7-12.5). Median days to ANC ≥ 0.5 × 109/L and platelet count ≥ 20 × 109/L were 10 (range 8-44) and 9 (7-141), respectively. There was no grade IV or V toxicity. The most commonly observed toxicities were grade I or II nausea and vomiting (77%), mucositis (67%), and diarrhea (55%)., Reversible grade III liver enzyme abnormalities were observed in 4% of patients; one patient developed reversible VOD. With a median follow-up of 2.1 years (range 0.2-4.3), the cumulative incidence of treatment-related mortality (TRM) at 100 days, 1 year, and 2 years was 1.0%, 3.1%, and 4.3%, respectively. Among patients with non-Hodgkin's or Hodgkin's lymphoma, the overall response rate was 90%, with 1- and 2-year PFS rates of 63% and 58%, respectively; 1- and 2-year OS rates were 90% and 82% respectively (Figure 1). PFS was significantly better in patients with chemo-sensitive lymphoma, 61% vs. 42% at 2 years, p=.03. Among patients with multiple myeloma, the overall response rate was 58%, with 1- and 2-year PFS rates of 67% and 44%, respectively; 1- and 2-year OS rates were 90% and 82%, respectively. Survival rates were not significantly different between the chemo-sensitive and chemo-refractory multiple myeloma patients. Conclusion Intravenous busulfan-melphalan is well-tolerated, and the individualized PK-directed dosing of i.v. busulfan likely contributes to the low toxicity profile of this regimen. The high response rate and disease control in patients with advanced disease is encouraging, and should be explored in larger phase II studies. Disclosures Andersson: Otsuka Pharmaceuticals: Consultancy.

Description: Backround: Arsenic trioxide (ATO) has been shown to be synergistic with melphalan both in vitro and in vivo. We conducted a phase I/II trial to determine the safety and efficacy of a combination of arsenic trioxide, melphalan and ascorbic acid (AA) as preparative regimen in patients undergoing high-dose therapy (HDT) and autologous hematopoietic progenitor cell transplantation for multiple myeloma (MM). We also assessed the impact ATO levels on melphalan pharmacokinetics (PK), engraftment and toxicity. Methods: Forty-eight patients with secretory myeloma (23 females, 25 males; median age: 54, range: 3570) were treated between 4/04 and 8/05. All patient received melphalan 100 mg/m2 IV on days -4 and -3 and AA 1000 mg/day IV on days -9 to -3. Patients were randomized to 3 arms; no ATO (arm 1), ATO 0.15 mg/kg IV on days -9 to -3 (arm 2) and ATO 0.25 mg/kg IV on days -9 to -3 (arm 3). Twelve patients had disease progression or relapse after a prior autograft. Median CD34 cells dose infused was 4.5 x 106/kg (range 2.3–10.9). Results: Patients in all 3 arms were evenly matched. With a median F/U of 14.0 months (range 6–25) post autograft, no dose-limiting toxicity or non-relapse mortality was seen. Toxicity was limited to grade I or II nausea, vomiting and diarrhea. Median ATO levels on day 0 in arms 1, 2 and 3 were 0.2, 26.3 and 46.2 ng/ml, respectively. Melphalan PK was not altered by ATO pretreatment. Median time to neutrophil engraftment (ANC 〉500/ dl) was 9 days. There were no engraftment failures or delays in the ATO arms. CR rate for the entire group was 23%, and total response rate (CR + PR) was 75%. 1-year Progression-free survival (PFS) and overall survival (OS) were 75% and 95%, respectively. There was no significant difference in CR, RR, PFS or OS between the 3 arms (p = 0.9, 0.9, 0.4 and 0.6, respectively). A prior autologous transplant (p = 0.02) and abnormal cytogenetics at transplant (p = 0.04) were associated with a significantly shorter remission. Conclusions: ATO + melphalan + ascorbic acid is a safe, effective and well tolerated preparative regimen for patients with multiple myeloma undergoing an autotransplant. A longer follow up is needed to assess the impact of ATO on progression-free and overall survival.

Description: INTRODUCTION More active high-dose regimens are needed for non-Hodgkin’s (NHL) and Hodgkin’s lymphomas (HL), where standard BEAM offers poor results in refractory or poor-risk relapsed tumors. We previously developed a regimen of infusional gemcitabine with busulfan and melphalan (Gem/Bu/Mel), exploiting the synergy between gemcitabine and alkylators based on inhibition of DNA damage repair. Gem/Bu/Mel was safe and highly active against refractory lymphomas (Nieto, BBMT 2012). To further increase its activity we combined it in preclinical experiments with SAHA, which induces relaxation of the chromatin and renders DNA more accessible to DNA-targeting agents. Concurrent exposure to SAHA and Gem/Bu/Mel resulted in markedly increased apoptosis and cytotoxicity in refractory B- and T-NHL lines, with increased PARP1 cleavage and γ-H2AX reflecting increased DNA damage (Valdez, Exp Hematol 2012). SAHA has a dose-response effect in refractory lymphoma lines up to clinically achievable levels with doses of 1,000 mg, higher than its usual dose. We wished to clinically study the concurrent combination of SAHA and Gem/Bu/Mel in refractory NHL and HL. Methods Patients ages 12-65 with refractory lymphomas and adequate end-organ function were eligible for this dose-finding study of SAHA combined with Gem/Bu/Mel. SAHA was given on days -8 to -3 at 200-1,000 mg PO daily (levels 1-11), preceding all chemotherapy. Gemcitabine was given as a loading dose of 75 mg/m2 followed by infusion at a fixed dose rate of 10 mg/m2/min over 3.5 (levels 1-5), 4 (level 6) or 4.5 hours (levels 7-11) on days -8 and -3. Each gemcitabine dose was immediately followed by the corresponding dose of busulfan or melphalan. After a test dose on day -10, busulfan was given from days-8 to -5 targeting a daily AUC of 4,000. Melphalan was infused at 60 mg/m2/day on days -3 and -2. ASCT was on day 0. Patients with CD20+ tumors received rituximab (375 mg/m2) on days +1 and +8. Dose limiting toxicities (DLT) were defined as any G4-5 nonhematological organ toxicity, or as G3 skin or G3 mucositis lasting 〉3 days at peak severity. Dose escalation followed a Bayesian design targeting a maximal DLT probability of 20%. Results Between 10/11 and 6/13, 66 patients were enrolled with DLCL, HL and T-NHL (Table 1). SAHA was escalated up to 1,000 mg PO daily, combined with full doses of Gem/Bu/Mel without encountering DLTs. There were no treatment-related deaths. The toxicity profile was manageable, including mucositis (48% G2, 31% G3), skin (11% G2, 3% G3), self-limited transaminase elevation (30% G2, 6% G3), and self-limited elevation of bilirubin not associated to VOD (22% G2, 16% G3). There were no cardiac, pulmonary, renal or CNS toxicities. There was no QT prolongation detected after SAHA. Neutrophils and platelets engrafted promptly at median days +10 (range, 8-13) and +12 (range, 8-55), respectively. This toxicity profile is undistinguishable from the one we previously described with Gem/Bu/Mel. Activity and patient outcomes at median follow-up of 8 months (1-23) are shown on Table 2 and Figures: Conclusions Concurrent administration of SAHA with high-dose GemBuMel is feasible up to a daily dose of SAHA of 1,000 mg, with no increased toxicities compared to Gem/Bu/Mel alone. Early results indicate that SAHA/Gem/Bu/Mel is highly active in refractory or poor-risk relapsed HL and DLCL and warrants further study in earlier disease stages. Longer follow-up is needed to confirm these findings. Disclosures: Nieto: Otsuka Pharmaceuticals: Research Funding. Off Label Use: Vorinostat not approved for DLCL or Hodgkin's lymphoma. Qazilbash:Otsuka Pharmaceuticals: Research Funding. Andersson:Otsuka Pharmaceuticals: Research Funding.

Description: Abstract 4200 Graft-vs.-Host Disease (GVHD) remains a common complication following matched sibling and unrelated donor hematopoietic cell transplantation (HCT). Standard GVHD prophylaxis calls for prolonged immune suppression, typically with a calcineurin-inhibitor. Recently, post-transplant cyclophosphamide (CY) has been studied as sole prophylaxis in matched related and unrelated bone marrow (BM) transplant recipients following an ablative conditioning regimen with busulfan (Bu) and CY and demonstrated comparable rates of acute GVHD and lower rates of chronic GVHD as traditional GVHD prophylaxis regimens. We recently conducted a phase II study of post-transplant CY following a reduced-intensity conditioning (RIC) regimen of Busulfan (Bu) and Fludaribine (Flu) in matched related and unrelated donor transplants and performed a matched-control analysis comparing their results with patients who received traditional GVHD prophylaxis with tacrolimus and mini-dose methotrexate (MTX) during the same time period. Forty-nine (49) patients were enrolled onto this study. They received Flu at a dose of 40mg/m2 over 1hour followed by intravenous Bu over 3 hours targeting a daily AUC of 4,000 microMol-min on days –6 to –3. Recipients of unrelated transplants received ATG on days –3 to –1 (total dose 4 mg/kg). CY was given as sole GVHD prophylaxis at a dose of 50 mg/kg on days +3 and +4. During the same period of time, 133 patients received a RIC regimen with intravenous Bu/Flu or Flu and melphalan (Mel) and received GVHD prophylaxis with tacrolimus plus mini-dose MTX (10mg/m2 on day +1, 5mg/m2on days +3, +6, +11). Unrelated donor transplants also received ATG. A computer generated algorithm was used to identify a comparable control group from our departmental database matching, in order of priority, on age, diagnosis, disease status, donor (matched-related versus unrelated) and graft source (PB versus BM). Matched controls (control group) were successfully identified for 37 study patients (Post-Cy group). Results: The median age for the Post- CY group and control group was 61 (range, 39–72) and 62 years (range, 37–72). Eight-one (81) % of patients in both groups had AML or MDS, 3% had ALL and 16% had NHL or CLL. Fifty-nine (59) % of patients in both groups had unrelated donors and received ATG in the conditioning. Disease status for the Post-CY and control groups respectively were CR1: 14 and 14%, CR2: 8 and 11%, 〉CR2: 38 and 32% and Primary Induction Failure / Untreated: 40 and 32%. Seventy (70) % of the post-CY group received BM versus 48% of the control group, whereas sex mismatching (Male donor for Female patient) occurred in 22% of the post-Cy and 8% of the control group. The cumulative incidence of grade II-IV acute GVHD and chronic GVHD in the post-CY and control groups were: 46% versus 19% (Hazard Ratio (HR): 2.8, 95% CI, 1.1–6.7; p=0.02) and 14% versus 21% (HR: 0.8, 95% CI, 0.2–2.6, p=0.7). Grades III/IV acute GVHD occurred in 14% (95% CI, 6–32) of the patients in the post-CY group whereas there were no cases of grade III/IV in the control group (p=0.02). Overall, progression-free and non-relapse mortality at 2-years are shown in the table below. Conclusion: Post-transplant CY following RIC is associated with higher rates of acute GVHD, with resultant trends for higher non-relapse mortality and lower overall survival when compared to tacrolimus and mini-dose MTX. The use of post-transplant CY as a sole GVHD prophylaxis regimen should be avoided following RIC transplant in matched-related and unrelated donors. Disclosures: Off Label Use: azacitidine: off-label use as maintenance therapy following allogeneic stem cell transplant for MDS/AML.

Description: A landmark study from Medical Research Council/Eastern Cooperative Oncology Group showed improved survival (∼53%) for patients allocated to sibling HCT versus either consolidation/maintenance chemotherapy or autologous HCT. Matched unrelated donors (MUD) are an option for patients without a SIB available and we retrospectively analyzed disease outcomes after SIB and MUD in adult ALL patients. Between 2001and 2012, 204 adult ALL patients with a median age of 36 years (range, 18-64) were transplanted with a SIB (n=112) or 8/8 MUD (n=92). Disease status at HCT was first or second complete remission and beyond (CR1, n=113, 55.5% and CR2+, n=91, 44.5%). Conditioning was myeloablative in 177 (86.8%) and reduced intensity (RIC) in 27 patients (13.2%). All but 2 patients received graft versus host disease (GVHD) immunosuppression with tacrolimus and methotrexate. Patient and disease characteristics including age, sex, histological subtypes and high risk disease features (WBC and cytogenetic classification at diagnosis), disease status at HCT and conditioning intensity were similar between SIB and MUD recipients. As expected, MUD patients had bone marrow (BM) as the stem cell source more commonly than SIB (69.6% vs. 7.1, p

Description: CBT is frequently complicated by delayed and failed engraftment when compared to other sources of hematopoietic stem cell support. Strategies to improve engraftment include double CBT and ex-vivo expansion. We are comparing these approaches in a randomized, prospective fashion. Patients (N=71) were randomized to receive either two unmanipulated (UNM) CB units (N=36) or one UNM unit and one unit which was EXP ex-vivo (N=35). The majority of CB units were 4/6 HLA matches. Methods: Diagnoses were AML/MDS (N=25; 35%), ALL(N=17; 24%), NHL(N=10; 14%), HD(N=7; 10%), CML (N=5; 7%), and CLL(N=7; 10%). Patients (Table 1) had primarily advanced disease, with a median of 3 (1–8) prior regimens including autotransplants in 22%. Preparative regimens included ATG and either myeloablative fludarabine plus dose-adjusted busulfan (N=13; myeloid diseases), or melphalan and thiotepa (N=28); patients not eligible for high-dose therapy received non-myeloablative fludarabine plus cyclophosphamide and 200 Gy TBI (=27) or melphalan (n=3). GVHD prophylaxis was tacrolimus plus either 3 doses of 5 mg/m2 methotrexate or MMF (table 1). Ex-vivo expansion: the smallest unit was CD133-selected using the CliniMACS device (day −14). The T cell-containing CD133-negative fraction was frozen. The CD133+ fraction was cultured for 14 days in media containing SCF, G-CSF and TPO. On day 0, the 2nd UNM unit was infused, followed by the CD133-negative and the EXP fractions. Results. Infused median total nucleated cells (TNC)×107/Kg was 3.5 and 3.6, and median CD34×105/Kg was 1.8 and 1.1, respectively for EXP and UNM pts. Median TNC fold-expansion was 23 (0.44–275) and for CD34+ cells, 2.3 (0–957). The median ex-vivo fold expansion of patients that engrafted platelets was higher than patients that did not engraft (23 (range, 0.4–275) versus 9.3 (range, 1.1–63), P=0.4). Patients that received EXP cells and a reduced-intensity regimen engrafted neutrophils in a median of 7 days (range, 4–15 days; n=14) versus 14 days (range, 5–32 days; n=12) in the UNM arm (P=0.05). Thirty-four patients are alive (48%) with a median follow up of 11.3 mo (range, 2–49 months). Twenty-four patients have relapsed (34%). Chimerism analysis showed that ultimately one CB unit dominated in all patients, on both the UNM and EXP arms of the trial. For the EXP arm the majority of patients had evidence of expanded CB chimerism posttransplant ranging from 7–82%. In half of those patients, the expanded CB unit predominated over the unmanipulated unit for 2–12 months posttransplant (52–87%), followed by gradual predominance of the unmanipulated CB unit by 14 months in all patients. Conclusion: Conclusion: EXP CBT was safe. The range of fold-expansion was highly variable. Accrual continues and we are focusing on strategies which improve CB expansion. Expanded Unmanipulated P Complete remission at UCBT 41% 59% 0.09 Median weight 85 (20–168) 76 (15–144) 0.18 Median age 43 (4–70) 38.1 (2–73) 0.4 Ablative preparative regimen 47% 68% 0.09 GVHD prophylaxis with methotrexate 32% 30% NS Time to ANC500 (median/95%CI) 14 days (4–32) 17 (5–45) 0.2 Proportion engrafting ANC500 80% 86% NS Time to PLT20K (median/95%CI) 34 (4–70) 34 (27–134) NS Proportion engrafting PLT 69% 55% 0.2 1-year survival 60% (40–75) 46% (27–63) 0.2 2-year survival 55% 20% 0.1 aGVHD gd II–IV/III–IV 43%/7% 43%/17% NS C.Incid. cGVHD 45% (28–78) 25% (15–65) 0.1 C.Incid.: cumulative incidence