ALBERT

Description: TRM, drug toxicities, life-threatening infections, poor quality of life, and graft versus host disease (GVHD) are significant risks of hematopoietic cell transplantation (HCT). In addition to the risks of HCT, existence of pre-transplant comorbidities can have significant impact on transplant outcomes. A comparison of CCI and the HCT-CI revealed that HCT-CI was prognostic and better at predicting TRM and overall survival (OS). However, the HCT-CI and CCI results have been inconsistent in predicting the TRM and OS in validation studies. In subgroup analyses of a large retrospective trial, HCT-CI did not predict TRM or OS for UCB recipients. Patient heterogeneity in age, disease, disease-risk, comorbidities, and conditioning regimens may have limited validation in these UCB recipients. The design of this research was to explore whether or not the HCT-CI and/or CCI can accurately predict post-transplant outcomes in young patients with high risk hematologic malignancies undergoing uniform RIC UCB transplantation. A retrospective chart review was performed on 52 consecutive young (age 〈 55) UCB transplant recipients receiving the RIC regimen fludarabine, cyclophosphamide, ATG, and 200 cGy TBI. All patients had received cyclosporine and mycophenolate mofetil for GVHD prophylaxis. Information on pre-transplant comorbidities was obtained from the CIBMTR pre-TED form for each patient and retrospective chart reviews. Demographic information, ECOG performance status (PS), identification of comorbidities, and post-transplant outcomes were obtained. Between 2005 and 2011, 52 patients age 19 – 54 (median 38) years, 30 males (58%) and 22 females (42%), underwent RIC UCB transplantation with the above regimen. Most patients had advanced stage or high risk hematologic malignancies; 28 patients had MDS/AML (54%), 8 patients had ALL (15%), while 16 patients had other hematologic malignancies. 39 patients had a PS = 0, while 13 had a PS = 1. Half of the patients were in CR 〉 2, with the same number receiving more than 2 prior therapies. 8 patients had received a prior autologous HCT, 8 a prior allo-HCT, and one patient had failed a previous UCD transplantation. 11 patients did not achieve engraftment. Median time to neutrophil engraftment was 26 days (95% CI: 24 – 28 d) and median time to platelets engraftment was 38 days (95% CI: 31 – 45 d). No patient developed grade 4 acute GVHD. Grade 3 acute GVHD was seen in 12 / 52 patients (23%). Chronic GVHD was seen in likewise seen in 12 patients (23%). To date 16 patients (30%) have relapsed. OS was 42% and PS was 37% at one year. Median PFS and median OS were 5 months and 7 months, respectively (PFS 95% CI: 1 – 11 months, OS 95% CI: 1 – 13 months). Neither CCI, nor HCT-CI were significant predictors of OS and PFS, however the ECOG PS was significantly associated with an improved OS and PFS (Table).OSPFSN1 yr2 yrs4 yrsp1 yr2 yrs4 yrspECOG PS03946%36%21%0.02644%36%21%0.0311331%0015%00CCI≤ 23944%26%10%0.2238%26%10%0.2〉 21338%31%31%38%31%31%HCT-CI02236%31%5%0.3632%32%5%0.3211443%14%14%29%14%14%≥21643%31%31%44%31%31%TRM occurred in 18 patients (35%). Neither comorbidity indices, nor the performance status were correlated to TRM (p 〉 0.05). For ECOG PS, OR 1.6 p = 0.49, CI 0.42 - 5.93; CCI OR = 2.4, p = 0.09, CI 0.86 - 6.59, HCT-CI OR = 0.6, p = 0.46, CI 0.19 - 2.08. In a previous presentation our group concluded that CCI performs better than HCT-CI in elderly patients undergoing UCB transplant. When tested in a population younger than 55 years old though, we were unable to validate the generally accepted prognostic indices. It is unclear whether this is due to a selection bias: it appears most of the patients were essentially health from a non-hematological stand-point, and as such the “classic” cardiac or pulmonary risk factors were underrepresented. The excess TRM is likely due to the severity of their underlying disease, and the majority were in CR ≥ 2 and had received multiple previous courses of antineoplastic chemotherapy. As umbilical cord transplants become more utilized, a new prognostic index needs to be developed, more fitting to the patients 〈 55 years old. Disclosures: No relevant conflicts of interest to declare.

Description: Retrospective analyses of UCBT using early historic controls show more robust graft vs leukemia effect in recipients given two-units vs one-unit. We present herein analyses from this single institution, prospective phase II clinical trial conducted 9/2003 to 5/2008 comparing 1 vs 2 unit UCBT in patients (pts) with high-risk, recurrent hematologic malignancies treated with reduced-intensity conditioning. The number of units infused in each pt was determined by biologic assignment based on the number of cells contained in the primary unit. Pts received 1 UCB unit if the cell dose was ≥ 2.5 x 107 nucleated cells/kg recipient weight and 2 UCB units for a minimum total combined cell dose of 1.5 x 107 cells/kg recipient weight if only smaller units were available. The UCB grafts were matched at ≥ 4/6 HLA loci (antigen level matching at class I A and B loci, and allele level matching class II DRB1 loci) except for 1 pt (3/6). If 2 UCB units were used they needed to be at least a 4/6 match to each other. The conditioning regimen included: Fludarabine 35 mg/m2/d x 5 days, cyclophosphamide 1 g/m2/day x 2 days, ATG 30 mg/kg/day x 2 days and single fraction TBI 200 cGy. Thirty-seven pts, 14 females, 23 males, median age 49 (range 20–71) years were enrolled. Most pts had advanced stage or high-risk hematologic malignancies; 28 pts (76%) had MDS/AML and 9 (24%) had other hematologic malignancies. Two pts underwent 2 transplants on this study after relapsing following the first UCBT. Twenty-seven pts received 1 unit and 10 pts received 2 units. The median follow up for survivors is 17.9 (range 1.2–55.9) months (mos) and median follow up for all pts is 10.1 mos. Median time to an ANC 〉 500/μL on 3 consecutive evaluations was 24.5 (range 12–55) days and 25 (range 13–43) days for 1 and 2 units, respectively (p=0.361). Median time to platelets 〉 20,000/μL without transfusion support on 3 consecutive evaluations was 38.5 (range 24–84) days and 63.5 (range 38–117) days for 1 and 2 UCB units, respectively (p=0.009). Median event-free survival (EFS) and median overall survival (OS) did not differ comparing 1 vs 2 units: 127 (range 16–1785+) days and 216 (range 16–1785+) days for 1 unit UCBT vs 92.5 (range 27– 1545+) days and 112 (range 27–1545+) days for 2 unit UCBT. The Kaplan-Meier (K-M) OS for 1 unit UCBT was 35.6% at 4 years compared to 33.3% for 2 unit UCBT (p=0.403). No statistically significant difference in K-M 4 year EFS was seen (p=0.894). At day +100, 7 pts (26%) had progressive disease or died in the 1 unit UCBT arm compared to 5 pts (50%) in the 2 unit UCBT arm. To date 51.8% of pts in the 1 unit arm have relapsed compared to 30% in the 2 unit arm (p=0.288). A total of 15/27 pts (56%) in the 1 unit UCBT arm died and 6/10 (60%) in the 2 unit UCBT arm died. Treatment-related mortality occurred in 3/10 pts in the 2 unit UCBT arm vs 2/27 in the 1 unit UCBT arm. Chimerism analyses were performed by VNTR analyses of blood mononuclear cells to confirm donor engraftment. Ten pts failed to achieve 〉 60% donor chimerism by day T+42, 8/26 in the 1 unit arm and 2/9 in the 2 unit arm (p=0.625). One pt died in each arm prior to T+42. Primary engraftment failure was defined by failure to restore donor or pt hematopoiesis requiring UCBT with the back up graft. Notably, 4 pts had primary and 1 pt had secondary engraftment failure in the 1 unit UCBT arm while no engraftment failures were observed in the 2 unit UCBT arm. No pts had grade 4 acute GVHD and no differences for overall incidence acute GVHD were noted comparing 1 vs 2 unit UCBT. Grade 3 acute GVHD was seen in 5/26 (19%) pts in the 1 unit UCBT arm and 3/10 (30%) in the 2 unit UCBT arm (p=0.658). Chronic GVHD was seen in 3 of 23 (3 limited) evaluable 1 unit UCBT pts and 2 of 7 (1 limited, 1 extensive) 2 unit UCBT pts. Pts who received a 2 unit UCBT had increased number of CD3+ cells (p=0.011) and total nucleated cells (TNC) (p

Description: Abstract 2019 High-dose chemotherapy (HDC) followed by autologous hematopoietic cell transplantation (AHCT) has been shown to result in better outcomes than conventional salvage chemotherapy for treatment of relapsed Hodgkin (Lancet 2002;359:2065–71) and non – Hodgkin lymphoma patients (N Engl J Med 1995;333:1540–5). The relative efficacy of different conditioning regimens is still uncertain. Our center has had extensive experience with BEP, consisting of BCNU (600mg/m2), etoposide (2400mg/m2) and cisplatin (200mg/m2) (Lazarus HM, J Clin Oncol 1992;10:1682–9) with more than 150 patients transplanted using this conditioning regimen. We have observed it to be efficacious and associated with a low incidence of transplant-related mortality (Biol Blood Marrow Transplant 2005;11:13–22). The purpose of this analysis is to compare the outcomes of patients transplanted with BEP with a contemporaneous cohort of patients transplanted with BEAM (BCNU 300mg/m2, etoposide 800mg/m2, cytarabine 1600mg/m2, melphalan 140 mg/m2). We performed a retrospective analysis of 55 consecutive relapsed lymphoma patients who had either BEAM or BEP preparative therapy for AHCT between 2005 and 2010 at our institution. Given the potential for nephrotoxicity and ototoxicity of cisplatin, patients were selected to receive BEAM if they had previous renal dysfunction (any elevation of serum creatinine) or had previous hearing loss. All patients received corticosteroids for prophylaxis of BCNU – induced pneumonitis. The Mann – Whitney test was used for analysis of continuous variables, Fisher's exact test for categorical data, while survival analysis was performed with the Kaplan – Meier method. Twenty-four patients received BEAM and 31 received BEP. The median age was higher in BEAM-treated patients (51 vs. 43 years, p = 0.0392). Other baseline characteristics were comparable between both cohorts: gender (male 54 vs. 58%, p = 0.791); diagnosis (NHL 75 vs. 77.4%, p = 1.000); status of disease at transplant (partial remission or worse 33.3 vs. 35.5%, p = 1.000); median number of previous therapies (2 in both groups, p = 0.51). The rate of non-renal comorbidities was higher in the BEAM cohort, but the difference was not statistically significant (45.8 vs. 32.3%, p = 0.403). The median CD34 cell dose was similar in both groups (6.252 x106 vs. 6.475 x106 CD34 cells/μL, p = 0.842). The rate of complications, including bacteremia, other infections, mucositis, diarrhea and renal dysfunction were not statistically different (Table 1). The small sample size may have prevented us from observing a statistical difference in cardiac toxicity.Table 1.Complications observed after BEAM or BEP conditioning for Autologous Hematopoietic CellBEAM (%)BEP (%)Bacteremia45.835.5p = 0.580Non – bacteremic infections37.541.9p = 0.787Mucositis54.258.1p = 0.791Diarrhea79.164.5p = 0.370Increase in serum creatinine 〉 50%12.516.1p = 1.000Cardiac complications16.73.2p = 0.153BCNU pneumonitis4.26.4p = 1.000 The median follow up time for the whole cohort was 31 months (28 vs. 34 months, p 0.267). Relapse free survival (RFS) after 36 months was 81.1% and 82.9% for BEAM and BEP, respectively (p = 0.693) (Figure 1). Overall survival at 24 months was 89.6% for BEAM and 90.8% for BEP (p = 0.371) (Figure 2). Among patients transplanted in partial response or worse, the median RFS was 57 months after BEAM and 66 months after BEP (p = 0.3173). There were no deaths in the first 100 days after transplant for both cohorts. There were no differences in the median number of days from hematopoietic cell infusion to discharge (12.5 vs. 12.0 days, p = 0.600) or achievement of ANC 〉500/μL (10 days for both cohorts, p = 0.415). In conclusion, BEP conditioning achieved comparable engraftment, toxicity and survival outcomes to those achieved by BEAM for treatment of relapsed lymphoma patients. BEP is therefore a valid alternative for treatment of this patient population. The BCNU dose in BEP is twice that in BEAM, but we continue to observe limited rates of BCNU – induced pneumonitis. BEP may be preferable over BEAM in patients with underlying cardiac comorbidity. Longer follow up and prospective trials will help in identifying variables that aid in the selection of patients for the most appropriate conditioning regimen. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Cytomegalovirus (CMV) reactivation remains one of the most serious complications after allogeneic hematopoietic stem cell transplantation (HSCT) occurring in up to 30-50% of HSCT recipients. CMV reactivation can lead to adverse outcomes including end-organ damage and graft failure. Prevention of CMV infection may improve outcomes of HSCT recipients; however, CMV reactivation can still occur in HSCT recipients despite receiving prophylactic acyclovir. In this study, we used prophylactic ganciclovir pre-transplant to reduce the incidence of CMV reactivation and CMV disease. Methods: To reduce the incidence of CMV reactivation and disease, ganciclovir was administered before transplantation (5 mg/kg twice daily intravenously from day −8 to day −2) for all donor and recipient seropositive allogeneic HSCT. This was followed by high dose valacyclovir or acyclovir starting day 0 until one year post-transplant. Patients were monitored weekly with serum CMV PCR through Day 100 post transplantation. Preemptive therapy was started for an elevated CMV viral load. CMV reactivation was defined as a CMV viral load of more than 135 IU/ml. Over the course of the analysis period, two different PCR methods were used for CMV viral load; since 2015 Roche Cobas AmpliPrep/Cobas TaqMan CMV test was implicated. CMV disease was defined as detection of CMV by one of the following diagnostic tests including: culture, immunohistochemistry staining, or histopathology examination accompanied by documentation of disease signs and symptoms of the affected organ. Statistical analysis was performed using SAS version 9.4. Logistic regression models were explored to assess the association of age, graft source, and disease type on CMV reactivation. We performed a retrospective analysis of all recipient or donor CMV seropositive patients who received their first allogeneic HSCT at the University of Virginia between 2012 and 2017. Results: Seventy-nine consecutive patients were treated. The median age was 58 years (range 20 to 72). The most common diagnoses were acute myeloid leukemia (n=39, 49%) and acute lymphocytic leukemia (n=11, 14% ). Graft sources were matched related donor, (n=24, 30%), matched unrelated donor, (n=28, 35%), haploidentical (n=4, 5%) and cord blood (n=23, 29%). 43 patients (55%) received myeloablative (CyTBI, BuCy and FluBu) conditioning. 36 patients (45%) received reduced intensity/nonmyeloablative conditioning (Flu/Cy/TBI+/- ATG, Flu/Cy/ATG ,Flu Mel, Flu Bu and Cy ATG). All patients received calcineurin inhibitor based prophylactic immunosuppressive therapy for GVHD prevention. 24 patients (30%) had CMV reactivation with median time of reactivation of 47 days post-transplant (range 27 to 229). 22 out of the 24 (88%) patients required treatment for CMV reactivation with a median treatment duration of 37 days (range 14 to 315). Patients were treated with either ganciclovir or foscarnet, as clinically indicated. The cumulative incidence of CMV reactivation at day 100 post-transplant was 27% with a 95% CI (18%-37%). The median highest viral load was 2130 copies/ml (range 151 to 3,250,000 copies/ml). There were no patients with biopsy proven CMV disease. There were no deaths attributed to CMV reactivation or disease. The median time-to neutrophil recovery (ANC 〉 500 k/uL) was 18 days and the median time to platelet count greater than 20,000 k/ul unsupported was 19 days. The incidence of acute GVHD (Grades II-IV) was 25 %. The incidence of significant acute kidney injury defined by serum creatinine of more than 2.5 mg/dL was 2.4 %. 1 year overall survival estimate was 54% with 95% CI (42-65%). In multivariate analysis, patients who received cord blood transplants, were approximately 4 times more likely to have a CMV reactivation (Odds Ratio 3.9 with a 95% CI(1.4-10.9)), p= 0.01, than those who did not. Conclusions:The incidence of CMV reactivation by day 100 of 27% with pre-transplant ganciclovir may be improved compared to historical controls of 30-50%.The use of pre-transplant ganciclovir was associated with no CMV disease, in this single center study.The use of pre-transplant ganciclovir is safe, with low incidence of kidney damage. These data suggest that pre-transplant ganciclovir with Preemptive therapy for viral reactivation should be considered regardless of graft source. Future prospective randomized trials are needed to evaluate strategies for CMV prophylactic regimens. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Clostridium difficile infection (CDI) is a major cause of morbidity and mortality in hospitalized patients. In autologous stem cell transplant (ASCT) recipients the national estimated incidence is approximately 5% to 10%. The use of antibacterial agents, such as ciprofloxacin, which historically has been used as a prophylactic agent in our autologous stem cell transplant population, is considered to be a risk factor for developing CDI. However, there have been few studies that have investigated the relationship of prophylactic antibiotics in the ASCT population and the development of CDI. One study, Satlin et al, found fluoroquinolone prophylaxis in ASCT patients decreased the rate of febrile neutropenia and blood stream infections and also a possible increase in the rate of CDI. Methods To attempt to decrease the incidence of CDI, our institution made a change to our standard of practice and suspended the utilization of CIP (500 mg twice daily beginning on the day zero and continued until engraftment or antibiotic escalation) for antibacterial prophylaxis in our ASCT population. All patients received antiviral and antifungal prophylaxis at baseline and broad-spectrum anti-pseudomonal antibacterial agents at the first recorded febrile event or as clinically necessary. CDI testing was completed when patients had three or more liquid stools in a 24-hour period along with other symptoms (i.e., fever, abdominal pain). Patients were found to have a CDI when the stool sample resulted positive while experiencing correlative symptoms. Stool samples were assessed for Clostridium difficile with the Cepheid GeneXpert NAAT. We retrospectively collected data on patients who received CIP prophylaxis from June 2016 - June 2017 and compared it to patients who did not receive CIP prophylaxis from July 2017 - June 2018. Data were analyzed using Chi-squared and T-tests were used to assess for significance and logistic regression was utilized to assess for possible associations between patient characteristics (age, race, sex, diagnosis, and conditioning regimen) and CDI. Results A total of 116 ASCT patients were analyzed; the median age was 57 years old and the most common diagnoses were multiple myeloma, non-Hodgkin's lymphoma, and Hodgkin's lymphoma; 57 patients received CIP antibacterial prophylaxis and 59 patients received no antibacterial prophylaxis. The most common conditioning regimens include melphalan (60%) and BEAM with or without rituximab (22%). CDI occurred in 15% of patients who did not receive CIP prophylaxis and 18% of patients who received prophylaxis (p=0.739). Of note, 88% of patients in both groups were tested for CDI. Neutropenic fever occurred significantly more often in patients who did not receive prophylaxis, 64% vs 35% (p=0.003). The rates of bacteremia were also found to be significantly higher in the non-CIP group, 32% vs. 12% (p=0.01). Gram-negative bacteria blood isolates were increased in patients not receiving CIP prophylaxis, 19% vs. 7% (p=0.062). Interestingly, there was also an increase in the occurrence of gram-positive bacteremia isolates, 19% vs. 5% (p=0.03). The average length of hospital stay was 19 days for both groups and intensive care unit admissions were similar between the two groups, 14% vs. 11% (p=0.616). Conclusion The lack of CIP prophylaxis in ASCT did not significantly decrease the rate of CDIs. With the removal of antibacterial prophylaxis, there was a significant increase in the rate of neutropenic fever and bacteremia, specifically gram-positive bacteremia. Hospital length of stay and admissions to the intensive care unit were similar between the groups. No additional risk factors were determined to be associated with the development in CDI in the patient population. Based on the results of this study, our institution reinstituted the utilization of CIP prophylaxis. Future studies include the utilization of antibody prophylaxis for CDI and also assessing Clostridium difficile colonization and its effect on developing an active clinical infection. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 5031 Background: Myeloma inevitably becomes refractory to available agents primarily due to accumulation of genetic and epigenetic mutations in the aberrant clone. The s-phase dependent DNA methylation inhibitor azacitidine may help overcome epigenetically mediated resistance in myeloma cells that cycle despite treatment and reactivate alternate growth control programs in cells with genetic apoptosis resistance. Here we present interim results of an ongoing phase I/II study that explores the safety, antimyeloma activity, and epigenetic effects of continuous azacitidine at predicted non-cytotoxic doses in combination with Rd in RRMM Methods: Entry criteria included measurable disease, relapsed or refractory state, and glomerular filtration rate ≥ 60ml/min (Cockroft-Gault). Lenalidomide 25mg d1–21 every 28d and dexamethasone 40mg weekly were fixed. In phase I (3×3 design) azacitidine was escalated from 30 to 40mg/m2 SC weekly (DL 1 and 2) to 30, 40, and maximally 50mg/m2 SC twice a week (DL 3–5). Dose limiting toxicity (DLT) was assessed during cycle 1 and response every 28 days according to IMWG uniform response criteria (partial response, PR, or better) and adapted EBMT criteria (minor response, MR). Plasma activity of cytidine deaminase (CDA) was measured in dose levels 3–5, using HPLC to quantify deamination of added cytidine (Wilcoxon exact test). Phase II enrolls 10 additional patients at the highest tolerated dose and includes global gene expression and DNA methylation arrays before and after cycle 1 in CD138+, CD34+, and remaining bone marrow cells. Results: Twenty patients with relapsed (n=1) or refractory (n=19) MM were enrolled after they had received a median of 4 prior regimens (range 1–10). Their disease was refractory to lenalidomide (n=17), bortezomib and/or carfilzomib (n=16), or both lenalidomide and proteasome inhibitors (n=14). 18 patients had received alkylators, 8 high dose chemotherapy, and 6 anthracyclines. One DLT was observed in 1 out of 6 patients treated at DL 4; neutropenic fever without other evidence for infection. No DLT occurred in 4 patients treated so far at DL 5. Grade 3 and 4 toxicities were seen in 11 patients, neutropenia in 9 (lowest ANC 0. 24K/mm3), thrombocytopenia in 4 (lowest 16K/mm3, transfusions used in 1 to avoid treatment delay), neutropenic fever in 2 (1 after cycle 1), and diarrhea, depression, deep venous thrombosis, and a possibly related pleural effusion with hypoxemia in 1 patient each. DL 1 and 2 (n=6) yielded only one MR, but as azacitidine was increased to twice a week (DL 3–5, n=14) the clinical benefit response rate (CBRR, ≥MR) and response rate (RR, ≥PR) increased to 35. 7% and 28. 6%, respectively with 1 very good partial response (VGPR), 3 PR and 1 MR. The patient with MR had secondary plasma cell leukemia (sPCL) after 7 prior regimens and had to be taken off trial due to cytopenias but was continued on reduced azacitidine (20mg/m2), lenalidomide (5–10mg), and prednisone (50mg TIW) reaching PR off trial and achieving a 10 month time to progression (TTP). Of all other responding patients, only the one treated with weekly azacitidine progressed while receiving azacitidine (TTP 3 months), one patient with sPCL progressed during azacitidine interruption for neutropenic fever, another patient was taken off trial due to pleural effusion with hypoxemia, 2 are still on study, currently for 8 and 3 months. The median time to response was 1 cycle (range 1–7). Responders in DL 3–5 had similar treatment histories as the entire cohort, refractory to last Rx: 80%, median previous regimens: 4 (range 1–7), refractory to lenalidomide: 60%, to proteasome inhibitors: 80%, and to both: 60%; but their plasma CDA activity was lower than in non-responders (Figure 1). Women treated at DL 3–5 (n=6) responded better than men (n=8), likely related to lower plasma CDA activity (Figure 2). Conclusions: Azacitidine was generally well tolerated up to the target maximal dose of 50mg/m2SC twice a week (BIW) in combination with Rd given to 4 out of 6 patients required for establishing the phase 2 dose. Encouraging response rates in refractory MM correlated with low plasma activity of the azacitidine inactivating enzyme CDA found predominantly in women. Results support development of azacitidine in RRMM and argue for testing combination with the competitive inhibitor of CDA, tetrahydrouridine. Until then, dose escalation in non-responding but tolerating patients will be explored. Disclosures: Reu: Celgene: Research Funding. Off Label Use: Azacitidine in multiple myeloma. Kindwall-Keller:Celgene: Speakers Bureau; TEVA: Speakers Bureau. Duong:Celgene: Research Funding.

Description: Background. Ispinesib is a novel polycylic, nitrogen-containing heterocycle small molecule that acts by inhibition of the mitotic kinesin spindle protein (KSP) HsEg5. Pre-clinical studies demonstrate activity against both murine and human solid tumor and leukemia cell lines by inhibition of adenosine diphosphate release from KSP, causing monopolar spindle formation and programmed cell death. Methods. This was a single agent, phase I dose-escalation trial in patients with relapsed/refractory acute myeloid (AML) or lymphoid leukemia (ALL) or advanced myelodysplastic syndrome (MDS). Intravenous ispinesib was given for 3 consecutive days every 21 days. Doses were escalated from 1.5 mg/m2/day to 13.3 mg/m2/day in cohorts of 3 patients. Clinical and peripheral blood responses were monitored on at least a weekly basis and bone marrow evaluations were done every three weeks. Grade 3 or greater non-hematologic toxicities were considered dose limiting toxicities (DLT) with the exception of infectious complications, electrolyte abnormalities or self-limited gastrointestinal toxicities. Results. Thirty-six adults (14 women, 22 men) with a median age of 66.5 years (range 28–82 years) were enrolled. The median number of previous induction treatments was 3, with a range from 0 to 8. Two patients had MDS, 5 had ALL and 29 had AML. Patients received a median number of 1.5 cycles of ispinesib, with a range from 1 to 5. The maximum tolerated dose (MTD) was determined to be 10 mg/m2/day given on 3 consecutive days. DLTs related to the study drug were grade 3 transaminitis and hyperbilirubinemia, and these developed in a total of 6 patients; one at dose level 3 mg/m2/day, 2 at dose level 7.5 mg/m2/day and 3 at dose level 13.3 mg/m2/day. Five patients developed self-limited grade 3 mucositis at dose level 13.3 mg/m2/day. Three patients died on study. One died due to disease progression, and two died both due to infection and hepatic dysfunction. None of the patients had normalization of their blood counts. Three patients with very high peripheral blast counts had rapid clearing of the blasts during treatment. Two patients had late bone marrow responses with less than 5% blasts at dose level 10 mg/m2/day after cycle 2 and cycle 3, respectively; both subsequently died of infection without count recovery. An additional three patients had a decrease in bone marrow cellularity with persistence of leukemic blasts. Conclusions. The MTD of ispinesib in this patient population and on this schedule was higher than that observed in prior trials of non-hematologic malignancies (30 mg/m2versus 18 mg/m2). The toxicity profile was different with DLT of hepatic toxicity in this trial and DLT of neutropenia in the solid tumor trials. Ispinesib appeared to provide myelosuppression in some patients at higher dose levels; however, there appeared to be minimal effect on the leukemic marrow component. Even in the majority of patients with myelosuppression, the leukemic clone persisted and proliferated following treatment. Ispinesib was effective at clearing the peripheral blood of blasts in a minority of patients. Ispinesib, given as a single agent in this trial on this schedule, is not an effective anti-leukemic therapy.

Description: In allogeneic hematopoetic cell transplantation (HCT) using myeloablative conditioning, the nucleated and CD34 cell doses were found to be of importance for several outcome parameters including survival, relapse and graft- versus- host disease (GVHD). Reduced intensity conditioning (RIC) HCT is increasingly used for older patients and for younger patients with co-morbidities. Peripheral blood progenitor cells (PBPC) is the predominant graft for RIC HCT. There is no large study of the effect of CD34 cell dose in the setting of RIC transplantation. Therefore, we studied the effect of CD34 dose on 1057 patients aged 45 – 75 years with acute myeloid leukemia (AML) or myelodysplasic syndrome (MDS) who received RIC regimen HCT between 2000 and 2011. Patients received grafts from HLA-matched siblings (n = 370) or from volunteer adult unrelated donors matched at the allele-level at HLA-A, -B, -C and –DRB1 (8/8; n = 522) or mismatched at 1 HLA-locus (7/8; n = 178). All patients received peripheral blood progenitor cells (PBPC), low dose TBI regimens (200 cGy) or alkylating agent plus fludarabine containing regimens. Separate analyses were conducted for HLA-matched and unrelated donor transplants. For HLA-matched sibling transplants (AML n=301; MDS n=69), exploratory analysis identified differences in survival for CD34 dose less than 4 x 106/kg. Multivariate modeling, adjusting for performance score, disease status, cytogenetic risk and transplant period, showed transplantation of PBPC with CD34 dose 〈 4 x 106/kg was associated with higher risks of overall mortality (HR 1.48, p=0.008) and non-relapse mortality (HR 2.03, p=0.004) compared to transplantation of PBPC with CD34 dose ≥ 4 x 106/kg. The effect of CD34 dose was independent of the other factors associated with mortality. The likelihood of neutrophil (HR 0.76, p=0.03) and platelet recovery (HR 0.76, p=0.03) was also lower with CD34 dose 〈 4 x 106/kg containing PBPC grafts. CD34 dose was not associated with acute or chronic GVHD or disease recurrence. In contrast, after unrelated donor transplantation (AML n=557; MDS n=130), the effect of CD34 cell dose on mortality was marginal. Exploratory analysis identified differences in survival for CD34 dose less than 6 x 106/kg. After adjusting for age, performance score, disease status, interval from diagnosis to HCT, and HLA-match, transplantation of PBPC with CD34 dose 〈 6 x 106/kg was associated with marginally higher risks for overall mortality (HR 1.20, p=0.05) and non-relapse mortality (HR 1.38, p=0.02) compared to transplantation of PBPC with CD34 dose ≥ 6 x 106/kg. There were no significant differences in hematopoietic recovery, acute or chronic GVHD and disease recurrence by CD34 dose. Further, we did not identify a CD34 dose for either donor source above which acute or chronic GVHD risks were higher. In conclusion, in the setting of RIC transplants for AML and MDS, the data support optimizing PBPC collections such that the CD34 dose delivered is in excess of 4 x 106/kg for HLA-matched sibling and CD34 dose in excess of 6 x 106/kg for unrelated donor transplants. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3006FN2 Transplant related mortality (TRM), drug toxicities, life-threatening infections, poor quality of life, and graft versus host disease (GVHD) are significant risks of hematopoietic cell transplantation (HCT). In addition, pre-transplant comorbidities can have significant impact on the transplant outcomes of elderly patients (pts). Two comorbidity measurement tools, the CCI and the HCT-CI have been inconsistent in predicting TRM and overall survival (OS) after conventional HCT. The HCT-CI and CCI scores have correlated less well with TRM and OS in UCB transplantation. These results may have been limited by the heterogeneity of the UCB transplantation study population in age, disease, disease-risk, comorbidities, and conditioning regimens used. This study was performed to explore the accuracy of the HCT-CI and CCI in predicting post-transplant outcomes in elderly pts with high risk hematologic malignancies undergoing uniform RIC UCB transplantation. A retrospective chart review was performed on 35 consecutive elderly (age ≥ 55 years (yrs)) UCB transplant recipients receiving the RIC regimen fludarabine, cyclophosphamide, ATG, and 200 cGy TBI. All pts received cyclosporine and mycophenolate mofetil for GVHD prophylaxis. Information on pre-transplant comorbidities was obtained from each pt's CIBMTR pre-TED form and retrospective chart reviews. Demographic information, ECOG performance status (PS), identification of comorbidities, and post-transplant outcomes were obtained. HCT-CI and CCI scores were distributed in the following comorbidity risk groups 0, 1, 〉 1. Between 2002 and 2011, 35 pts underwent UCB transplantation with the above regimen. Median age was 65 yrs (range 55–71), 21 were male (60%) and 14 female (40%). Most pts had advanced stage or high risk hematologic malignancies; 28 had MDS/AML (80%) and 7 had other hematologic malignancies. All pts had a PS ≤ 2. Twenty-seven pts were in CR ≤ 2, with 31 pts having received ≤ 2 prior therapies. Eight pts had received prior transplants, including 2 pts with prior UCB transplantations and 6 pts with prior autografts. UCB cell dose was calculated on actual body weight (median 84 kg, range 56.1–135.1 kg). A total of 66 UCB grafts matched at a minimum 3/6 (3/6 = 4, 4/6 = 34, 5/6 = 22, 6/6 = 6) were infused. Pts received a range of 1 to 5 UCB units (1 unit = 12 pts, 2 units = 19 pts, 3 units = 2 pts, 5 units = 2 pts). VNTR/FISH analyses confirmed engraftment with median time of 21 days (d) (95% CI: 14–40 d) to achieve 〉 60% chimerism. Nine pts failed to achieve chimerism 〉 60%, and 3 had secondary engraftment failure. Median time to ANC 〉 500/μL for 3 consecutive values was 27 d (95% CI: 21–32 d) and median time to platelets 〉 20, 000/μL on the first day of 7 consecutive days without a platelet infusion was 40 d (95% CI: 35–71 d). No patient developed grade 4 acute GVHD. Grade 3 acute GVHD was seen in 3/35 pts (9%) and chronic GVHD was seen in 6/27 pts (22%). To date 31% (n = 11) of pts have relapsed. Pre-transplant cardiac comorbidities, A-fib/flutter and coronary artery disease, were the most common. Six pts had prior solid tumor malignancies, not active at the time of HCT, including breast (n=2), prostate (n=2), bladder (n=1), and kidney (n=1). After a median follow up of 13 months (range 1–70), 1 yr OS and progression free survival (PFS) were 61% and 55%, respectively. Median PFS and OS were both 16 months (mos) (PFS 95% CI: 8–70 mos, OS 95% CI: 9–70 mos). CCI but not PS or HCT-CI was a significant predictor of OS and PFS (Table and Figure).OS (%)PFS (%)FactorN1 yr2 yr4 yrp-value1 yr2 yr4 yrp-valuePS    0175750330.885252350.81    1-218654534584538CCI    016805822675932    14100500.04100500.04    〉115333333333333HCT-CI    012544314564415    1108069690.296969690.25    〉113533535453636 TRM occurred in 8 pts (23%). CCI was associated with TRM (p=0.05): pts with CCI ≥ 2 had a 40% (6/15) TRM vs 10% (2/20) with CCI 0–1. PS (p=0.69) and HCT-CI (p=0.47) did not correlate to TRM. In conclusion, elderly pts undergoing RIC UCB transplantation for high risk hematologic malignancies, the CCI was a statistically significant predictor of TRM, PFS, and OS. This index and not HCT-CI or PS identified elderly pts undergoing RIC UCB transplantation at higher risk of TRM and poor post-transplant outcomes. Larger validation studies of the predictive capacity of these comorbidity indexes need to be performed in the multi-institutional setting. Disclosures: Cooke: Amgen:.