ALBERT

Description: Background: A major advance in allogeneic stem cell transplant (SCT) has been the establishment of effective and less toxic reduced intensity regimens as alternative therapeutic approaches for patients with certain hematologic malignancies. The focus of these approaches has been to reduce treatment related mortality (TRM) while providing sufficient host immunosuppression to permit the achievement of complete donor chimerism that leads to a graft versus tumor effect, resulting in long-term disease control and cure. In this study we report overall survival (OS), relapse rate (RR), and non-relapse mortality (NRM) in patients receiving reduced intensity conditioning (RIC) with a 48 hour continuous infusion of busulfan with fludarabine followed by methotrexate (MTX) alone or with lympho-depleting anti-CD52 monoclonal antibody (mAb), alemtuzumab, or T cell depleting immunoglobulins, anti-thymocyte globulin (ATG) given as graft versus host disease (GVHD) prophylaxis. Methods: Patients with histologically confirmed hematologic malignancies, who were over the age of 55, or otherwise ineligible for more intensive busulfan-based therapy were enrolled on a Phase II protocol, LCCC 0306, at the University of North Carolina. All patients received IV fludarabine 30 mg/m2/day on days-7 through-3; busulfan 6.4 mg/kg by continuous infusion over 48 hours on days-6 through-5 and tacrolimus from day-1 plus either MTX alone, ATG or alemtuzumab alone, or a combination of these agents depending on disease risk and donor status. Results: 71 patients were enrolled. The median age was 58 (range 28 - 69). 58% were men and 42% women. 37 patients received HLA-matched related donor (MRD) stem cell grafts, and 34 patients received either matched unrelated donor (MUD) or HLA-mismatched grafts. The median HCT-Comorbidity Index (CI) score was 3 (range 0 - 8, HCT-CI score: 0 = 12 pts, 1 - 2 = 22 pts, ⪴ 3 = 36 pts). The majority of pts were intermediate risk by Disease Risk Index (DRI) score (9 low, 40 int, 19 high, 1 very high, 2 undetermined). The DRI low/int group had an estimated 18 month OS of 65% (CI 0.50 - 0.77), and DRI high/very high OS was 35% (CI 0.16 - 0.55). Estimated median survival time based on DRI for low/int was 1674 days (CI 646 - 2920) versus 375.5 days (CI 136 - 1018) (p = 0.003) for DRI high/very high pts. OS at 18 months in the MTX alone arm (n = 20) was 70% (CI 0.45 - 0.83), ATG (+/- MTX, n = 27) was 52% (CI 0.32 - 0.69), and alemtuzumab (+/- MTX, n = 24) was 46% (CI 0.26 - 0.64); (p = 0.17). The 18 month relapse rate for the MTX alone arm was 50% (CI 0.27 - 0.69), 41% in ATG (CI 0.37 - 0.76), and 41% in alemtuzumab (CI 0.36 - 0.77); (p = 0.85). The 18 month NRM in the MTX alone arm was 7% (CI 0.61 - 0.99), alemtuzumab (+/- MTX) was 32% (CI 0.42 - 0.85), and ATG (+/- MTX) was 27% (CI 0.52 - 0.86); (p = 0.05). Much of the increased NRM in the alemtuzumab and ATG arms was attributable to increased rates of fatal infectious complications: 1 in the MTX arm, 3 in the ATG arm and 8 in the alemtuzumab arm. No patients receiving MTX alone, 3 receiving alemtuzumab and 6 receiving ATG developed grade 3-4 acute GVHD. 5 of the 20 surviving patients have extensive chronic GVHD. Conclusion: Continuous infusion, reduced dose, busulfan and fludarabine can be safely administered to patients who are ineligible for myeloablative conditioning either because of age or comorbidities. The use of MTX alone with this regimen results in a median survival of over 4 years. Patients with high DRI or who received treatment with alemtuzumab or ATG had higher NRM and poorer OS irrespective of donor status. Disclosures Wood: Best Doctors: Consultancy; Inform Genomics: Consultancy.

Description: Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.

Description: Abstract 1940 INTRODUCTION: Dose escalation of chemotherapy and radiation in conditioning regimens has been associated with lower relapse rates but not significantly improved overall survival in allogeneic transplants because of higher treatment related mortality. The advent of IV BU has allowed more precise dosing of this drug and permitted dose escalation to a greater degree than in the past. METHODS: Test dose (.8 mg/kg) IV BU was administered one week prior to start of the conditioning regimen and the desired AUC calculated from the Bu clearance. Starting at a standard AUC of 4800/24 hours, target dose levels were escalated in 20% increments to 5760, 6912, 7603 and 8663 uM-min/24 hours. BU was administered from day −7 to −3 by 90 hour continuous infusion accompanied by fludarabine, 30 mg/m2/d on days −7 to −3. All pts received tacrolimus and either alemtuzamab alone or ATG+/− low dose MTX for GVH prohylaxis. Standard antibiotic prophylaxis and supportive care was provided. RESULTS: 55 high risk pts, median age 39 (22–54), 20 MRD, 35 MUD, 26 AML, 7 ALL, 2 APL, 1 biphenotypic leukemia, 8 MDS, 5 NHL, 2 HD, 1 CLL, 1 CML, 1 CMML, 1 MF were enrolled on this IRB approved study. 30 patients received alemtuzamab, 19 ATG + MTX and 6 MTX only. Mean achieved AUCs were 4973(14 pts), 5638(7 pts), 7131(25 pts), 7053(7 pts), and 8680(2 pts) uM-min/24 hrs. The MTD was dose level 3 (target 6912, achieved 7131 uM-min). Grade 4 DLTs were grade 4 mucositis in 2/2 at level 5 and 1/7 at level 4 and 1/7 reversible VOD at level 4. One additional grade 5 toxicity was seen at dose level 1(liver failure), level 2 (mucositis) and level 3 (VOD). The incidence of grade 4 or 5 VOD was 2/55 or 4%. Median AUC for the entire group was 6312 uMol-min with the median in the group below the overall median being 5484 and the group above the median being 7394 uMol-min/24 hours; a 35% difference in dose between the lower and higher median values and a 54% increase over a standard AUC dose of 4800 uMol-min. When analyzed by AUC, pts above the median had a higher median overall survival (OS), 353 days vs 183 days (HR.48, p =.058) for those below the median and longer relapse-free survival (RFS), 818 vs 187 days (HR.47, p =.039). When divided by AUC in tertiles (median AUC values of 5106 (19 pts), 6431 (19 pts), and 7693 (17 pts) uMol-min/24 hrs respectively), the median OS in days for each group were 298, 353, and Not Reached and median RFS were 191, 353, and 818 days. Three group comparison using Cox model yielded p-values of.063 and.053 levels for RFS and OS, respectively. 2-year OS and RFS for the below and above median groups were.27 and.20 and.62 and.57, respectively. 2-year OS and RFS for the lowest, medium and highest AUC groups in the tertile analysis were.24 and.20.41 and.35, and.70 and.63, respectively. In multivariable analysis, higher AUC dose, use of ATG rather than alemtuzamab and having a MUD all demonstrated a trend toward improved outcomes with AUC being the strongest predictor. CONCLUSION: High AUC levels of busulfan can be safely achieved with targeted PK dosing and continuous IV infusion leading to improved overall survival and decreased relapse rates in patients undergoing allogeneic transplantation with either ATG or alemtuzamab as part of their GVHD prophylaxis. Disclosures: Shea: Otsuka Pharmaceuticals: Research Funding.

Description: Abstract 4550 Latent viral infections occurring in the post bone marrow transplant period remain a significant clinical problem. New and effective antiviral drugs (AVD) are needed to provide adequate therapy for infected patients. We report the use of a new oral AVD, CMX001 (Chimerix Inc. Durham, NC) to treat DNA virus infections in six severely ill patients.Pt #123456Adeno Blood (PCR Cycles)Pre: 30.6Pre: 33.1Post: 37.3Post: NegBK polyoma virus Urine (log copies/mL)Pre: 4.89Pre: 4.86Pre: 6.54Pre: 9.06Post: 7.88Post: 5.99Post: 7.55Post: 7.16BKV BloodCleared after 1 dosePre: No valueCleared at 6 doses;Post: detectableHHV6 Blood (PCR Cycles)Pre: 42Post: 39.9Dose (mg/kg) biw22444 reduced to 32StatusDied GVHDDied GVHDDied GVHD + SepsisDied GVHDAliveAlive All patients had grade 2 or greater gut graft versus host disease (GVHD) during or after CMX001 treatment. The Table shows viral levels before and after treatment with CMX001 twice/wk. Pt 1's AV cycle number fluctuated and never cleared. A higher cycle number indicates less virus. Pt 2 cleared AV from blood after first dose, but urine, stool, gut biopsies remained AV positive. Pt 3's HHV6 plasma PCR levels fluctuated, but the pericardial fluid levels had cleared at autopsy. Pt 4 did not have pre dosing blood BKV PCR levels taken and his subsequent blood BKV low level was measurable (below the positive limit level). Interestingly, however, the patient's BKV related hemorrhagic cystitis (HC) symptoms resolved after 4 doses of CMX001. Pt 5's BKV HC symptoms also resolved after 4 doses of drug, and his positive blood viral level cleared after 6 doses. Pt 6 discontinued drug because of abdominal pain and the need for NPO, but his hemorrhagic cystitis symptoms had abated. No specific toxicities were documented in these severely ill patients with gut GVHD, but gut pain and transient thrombocytopenia were observed. In summary, one of 2 pts with AV cleared their blood. BKV was not cleared from urine, but 2/4 cleared BKV from blood. One patient with HHV6 did not clear blood DNA viral levels, but did clear pericardial fluid. In both cases of HC, symptoms resolved. Thus, CMX001 shows promise as new antiviral drug given its ability to decrease DNA viral levels in this small group of critically ill patients. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2083 INTRODUCTION: The addition of chemotherapy to G-CSF for stem cell mobilization prior to autologous stem cell transplantation (ASCT) provides the potential for increased cell yield and improved mobilization outcomes relative to G-CSF alone. We have investigated the use of mid-dose VP-16 plus G-CSF in pts with lymphoma and examined whether plerixafor might be incorporated into this chemomobilization backbone in a cost-effective way for a population with inferior outcomes. METHODS: Between June 2004 and September 2010, 159 pts with lymphoma underwent ASCT following the use of VP-16 (375mg/m2 on D#1 and D#2) and G-CSF (5mcg/kg twice daily from D#3 through the final day of collection) for mobilization. 26 pts also received a dose of Rituximab (375mg/m2) on D#1. Stem cell collection was initiated when the peripheral blood CD34 cell count was more than 7 per ul. Data on costs for fixed and variable expenditures associated with mobilization and collection were calculated on an individual patient basis. Costs also included unexpected complications such as inpatient hospitalizations, antibiotic use and blood product transfusions. “Poor mobilizers” were defined as pts failing to collect 5 × 106 cells in one or two days. Univariable and multivariate logistic regression were performed to identify predictive models for poor mobilization and to identify hypothetical breakpoint scenarios for the cost-effective utilization of plerixafor. For the breakpoint scenarios, a median of 3 doses of plerixafor was assumed based on the published phase III data with plerixafor plus G-CSF. RESULTS: Of 159 pts with lymphoma, 90 (57%) were identified as “good mobilizers,” 43% were “poor mobilizers”, and 150 (94%) collected at least 2 × 10 6th/kg CD34 cells in total (83% within 4 apheresis sessions), comparing favorably to published data with G-CSF alone or G-CSF + plerixafor. 51 (32%) required PRBC or platelet transfusion, 10 (6%) were admitted to the hospital during the mobilization period, and 8(5%) required a second mobilization or bone marrow harvest. There was no increased incidence of secondary malignancies. Average costs were $14923 ($6121-$24546) for good mobilizers and $27044 ($12206-$51846) for poor mobilizers (p

Description: BACKGROUND: Hemorrhagic cystitis (HC) is a complication of hematopoietic stem cell transplantation, occurring in 10 to 70% of transplant recipients. Factors that may contribute to the risk of developing HC include intensive preparative regimens, especially those including busulfan, high-dose cyclophosphamide or ifosfamide, transplantation from matched unrelated donors, infection with adenovirus, and the development of graft-versus-host disease. The reactivation of latent BK virus in the kidney is thought to lead to the development of late-onset HC in hematopoietic stem cell transplant patients. Early reports of cidofovir’s efficacy in BK virus-associated HC used intravenous cidofovir, but treatment was often complicated or compromised by excessive toxicity, especially renal compromise. Based on small single patient reports of the use of intravesicular cidofovir in the management of other viral causes of cystitis, we evaluated the use of intravesicular cidofovir for the management of BK virus associated cystitis. METHODS: In patients undergoing stem cell transplant, BK viral loads were routinely monitored twice weekly. The presence of cystitis or hematuria in a patient with detectable BK viruria was considered the trigger for initiation of therapy. Patients were treated with cidofovir at a dose of 5 mg/kg. Drug was diluted with 60mL of normal saline and administered via foley catheter, which was clamped for one hour post administration. Weekly repeat dosing was allowed as long as symptoms persisted. In addition to symptom control, BK viral loads were measured before, during, and after treatment. RESULTS: Four patients were included in this initial evaluation. All were recipients of allogeneic stem cell transplants; three were recipients of matched unrelated donor transplants and one received a transplant from a matched sibling. Patients received between 1 and 4 doses of cidofovir for initial therapy. All 4 patients experienced complete resolution of symptoms. The range for symptom resolution ranged from 2 days to 3 weeks. Symptoms reappeared in only 1 patient after discontinuation of therapy. Monitoring of BK urine viral loads revealed that 3 of the 4 patients had a greater than 50% decrease in urine BK viral load with initial dosing of cidofovir, indicating presence of antiviral activity when the drug is administered by this novel route. CONCLUSION: Intravesicular cidofovir is safe, easy to administer, and associated with both elimination of symptoms and reduction in viral loads in patients with hemorrhagic cystitis following high dose therapy and allogeneic transplantation.