ALBERT

Description: HDC and AHSCT is an effective treatment option for patients with relapsed or refractory NHL. The outcome of this treatment depends on the histological grade (indolent versus aggressive) with a well documented time dependent difference in temporal relapse pattern. We developed statistical models to describe the time dependent outcome after AHSCT based on histologic grade and other variables. During January 1993 to December 2003, 114 relapsed or refractory NHL patients were treated at single institution using high-dose BCNU 600 mg/m2, etoposide 2400 mg/m2, and cisplatin 200 mg/m2 IV over 5 days and AHSCT. Median age was 53.5 (range: 25–70) years, 78 patients had aggressive NHL and 36 indolent NHL. Immediately before transplant, 75 patients received involved-field radiotherapy (IFR) to sites of prior bulky (〉 5 cm) disease. Twenty-seven patients had mobilized stem cell transplant (13 with in vivo purging and 14 with ex-vivo purging). At a median follow up of 33 (range: 3 to 118) months, the estimated 5 year Kaplan-Meier probabilities of overall survival (OS) and DSF were 61% and 51%, respectively. DFS was similar up to about 1.2 years between indolent and aggressive NHL (Figure 1). DFS of the group who had purged stem cells was improved marginally over non-purged group. Cox proportional hazards model was used to adjust for differences in baseline characteristics between grades that might affect DFS. The proportionality assumption of Cox model was tested by adding a time-dependent covariate for each variable. This showed that the proportionality did not hold for lymphoma grade, indicating the relationship between the grade and DFS differed over time. The results of piece-wise Cox model after controlling age, IFR, purging status indicate there was no difference of DFS between the grade groups up to 1.2 years (optimal cut-off point) post-transplantation (p = 0.748). However, the relative risk for experiencing relapse after 1.2 year in patients with indolent compared with patients with aggressive NHL was 4.22 (p = 0.006) with 95% confidence interval (1.5, 11.9). Our results statistically prove the previously described biological differences in outcomes of patients with indolent and aggressive NHL following HDC. The time-dependent effect of lymphoma grade on DFS indicates the need for early (within first year) incorporation of novel therapeutic approaches, such as post-transplant immunotherapy, tandem high-dose therapy and, allogeneic transplant to generate graft-versus-lymphoma effect, in management of patients with indolent NHL undergoing autologous transplantation. Figure 1: DFS by tumor grade. Figure 1: DFS by tumor grade.

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: Background: Autologous hematopoietic cell transplant (HCT) is frequently used to treat plasma cell dyscrasias. High-dose melphalan is the most commonly utilized preparative regimen. Frequently seen non-hematologic adverse effects include oropharyngeal mucositis and GI toxicity. Reported incidence rate of overall and severe (grade 3-4) mucositis is 60-90% and 30-40%, respectively. Amifostine is a thiol derivative, which has been used for protection of normal tissues in radiation and chemotherapy. Amifostine has a relatively safe profile with hypotension, nausea, vomiting and diarrhea (N/V/D) as main side effects. We explored the efficacy of amifostine to reduce overall incidence and severity of mucositis after high-dose melphalan therapy. Methods: We conducted a retrospective study of 126 autologous HCT (110 patients) with high-dose melphalan performed from January 2007 to July 2014 at our center for plasma cell myeloma. Twelve patients underwent tandem transplants and four had second autologous transplants after relapsed disease and were excluded from survival analysis. Patients' characteristics (n=110) as listed in Table 1. All but one patient received two doses of Amifostine given as 740 mg/m2 IV bolus on days T-2 and T-1. Melphalan was administered as IV bolus on T-1 at the dose of 200 mg/m2, except for 4 patients who received 140 mg/m2 due to impaired renal function. All patients received ice chips peri-melphalan infusion. All patients received cryopreserved autologous hematopoietic cell infusion on T-0. We graded mucositis and GI toxicities as per CTCAE v4.0 and recorded patient controlled analgesia (PCA), total parenteral nutrition (TPN), transplant and disease outcomes. Results: Severe (grade 3-4) mucositis and diarrhea rates were 14% and 12%, respectively (Table 2). PCA was used in 10% of transplants at a mean duration of 0.9 days and TPN was utilized in 5% of transplants for a mean duration of 0.45 days. Median length of stay for transplant was 15 days (range 3-44 days). Median time to neutrophil and platelet engraftment was 10 and 19 days, respectively (Table 3). Three patients died within 100 days after transplant (2 due to infections and 1 due to renal amyloidosis). At a median follow up of 39 months, median PFS is 25 months and OS is greater than six years. All patients were able to receive amifostine at prescribed doses except for one patient who received only one dose due to intractable N/V/D. Conclusion: Amifostine is effective in reducing high-dose melphalan-induced severe mucositis. Our data would suggest a decrease in severe mucositis and GI toxicity rates when compared to historically reported incidences. In addition, amifostine does not appear to have a deleterious effect on engraftment and/or survival and response rates (Table 3). Table 1. Patients characteristics Median Age (years) 59 (36-71) Gender (%) Male 54Female 46 Performance status (ECOG) 1 (0-2) Median time to transplant from diagnosis (years) 0.97 Median number of treatment regimens prior to transplant 2 (1-6) Response prior to transplant (%) Partial remission (PR)Very good partial remission (VGPR)Complete remission (CR)Stable disease (SD) 60%21%18%0.8% Table 2. Toxicity Overall (grade 1-4) Severe (grade 3-4) Median grade Median Duration (days) Mucositis 55% 14% 2 2 Diarrhea 92% 12% 2 7 Nausea 89% 4% 1 8 Vomiting 67% 3% 1 2 Table 3. Engraftment and post-HCT disease response Engraftment Median (days) Range (days) Neutrophils 10 6-21 Platelets 19 8-71 Post-HCT disease responses (%) Stringent complete response (sCR) 13% Complete response (CR) 32% Very good partial response (VGPR) 24% Partial response (PR) 25% Not evaluated 6% Disclosures Off Label Use: Amifostine use to prevent mucositis.

Description: Introduction: Targeting the maturation arrest in acute myeloid leukemia (AML) to induce differentiation instead of killing rapidly dividing cells can lead to more efficacious and less toxic therapies for AML. Inhibition of the GSK3 enzyme with lithium sensitizes AML cells to the differentiating effects of all-trans-retinoic acid (ATRA), resulting in differentiation and inhibition of proliferation (Gupta K, et al. and Wald DN. Leukemia. 2012;26:1277-85.). In vitroand animal studies suggest the combination of ATRA and lithium has therapeutic activity against AML. We are conducting a phase I study of ATRA and lithium for the treatment of relapsed, non-progranulocytic AML (NCT01820624). Methods: Eligible patients were older than 18 years of age and had relapsed /refractory non-progranulocytic AML. Lithium carbonate 300 mg by mouth thrice daily was started on day -3 and given continuously and was titrated to achieve a target plasma concentration of 0.6 – 1.0 mmol/l. ATRA, at a starting dose of 22.5 mg/m2by mouth daily in two divided doses, was given from day 1 through 7 and day 15 through 21 of a 28-day cycle. GSK3b activity was measured using flow cytometry-based assays with antibodies against its inhibited form: serine-9-phosphorylated GSK3β (pGSK3) in AML cells. phosphoGSK3α (pGSKα) and β-Catenin were also evaluated with flow cytometry. The AML blasts (CD34+CD38+) as well as AML stem cells (CD34+CD38-) were quantitated by flow cytometry and changes in surface markers (CD11b, CD14 and CD15) were followed after treatment. Results: Correlative data were available on the first 5 subjects. Median age was 67.5 (range 42-83) years; median number of prior therapies was 2.5 (range 1 - 6). Mean expression of pGSK3, compared to baseline, increased by 1.6-fold when the target lithium plasma concentration of 0.6 mmol/L was reached (95% CI 1.14- 2.07), whereas there was no increased expression at levels below 0.6 mmol/L (change in expression: 0.94; 95% CI 0.65-1.27). The difference between pGSK3 expression levels above and below the threshold was significant (p = 0.04). After 10 days of treatment, lithium plasma concentration and pGSK3b expression presented a positive correlation, with a Pearson correlation coefficient of 0.82 (p = 0.024, R20.67). The same cutoff value for lithium plasma concentration did not identify statistically significant differences in the expression of pGSK3α or β-catenin. The mean proportion of circulating blasts (CD34+) increased 4-fold after 4 weeks of treatment; correlating with the absence of clinical response in patients enrolled in this first cohort at low doses of ATRA. However, at the same time point, the proportion of leukemia stem cells (CD34+/CD38-) decreased to 38% of baseline (95% CI 21%-98%, p = 0.04). One subject presented evidence of differentiation after 1 week of treatment with the combination, with decreased blast expression of CD11b (from 20% to 3%) and CD15 (66 to 2%) and a concomitant 5-fold increase in CD14 expression in AML stem cells. An additional patient presented a 4-fold induction of CD15 expression in blasts, suggestive of partial AML differentiation. Conclusion: Lithium is capable of effecting GSK3β inhibition in vivo at plasma concentrations that are achievable in clinical settings. Study accrual continues and larger number of patients will allow for ROC analysis to determine the specific lithium concentration for optimal GSK3β inhibition. Treatment with the ATRA and lithium combination can decrease circulating AML stem cells and induce AML cell differentiation. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Umbilical cord blood transplantation (UCBT) is often complicated by delayed engraftment and higher rates of engraftment failure. We sought to investigate the outcomes of patients undergoing UCBT2 after engraftment failure compared to those who had autologous hematopoietic recovery and did not receive UCBT2. Methods We reviewed the medical records of 186 patients who received UCBT between 2001 and 2011 at the Case Comprehensive Cancer Center [Seidman Cancer Center, University Hospitals Case Medical Center and Taussig Cancer Institute, Cleveland Clinic]. Standard definitions of engraftment were used. Patients who died or had progressive disease before day 30 were excluded (n=9), as they were considered inevaluable for engraftment. Results Twenty-seven patients (15%) had primary engraftment failure; twelve had autologous hematopoietic recovery and 15 presented no recovery (Table). The median total nucleated cell dose for the first UCBT was 2.56x107 cells/kg (range 1.23 x107 - 5.69x107), not statistically different from patients achieving engraftment (p = 0.29). The cause of engraftment failure could not be identified in 22 patients. Among patients with engraftment failure without autologous recovery, 2 patients did not receive further salvage and died at 40 and 48 days after first UCBT; 2 others received backup autologous hematopoietic cell infusions and 11 received UCBT2. In patients with autologous hematopoietic recovery, 8 did not receive a UCBT2 because disease remission had been attained (n=4), active infection (n=1), relapsed disease beyond 40 days after UCBT (n=1) or absence of compatible donor (n=1). Fifteen patients (engraftment failure [n=11]); autologous recovery, [n=4]) underwent UCBT2, at a median of 43 days (range 33-244) from first to second UCBT. All patients received non–myeloablative second conditioning regimens. Four patients received one UCB unit and 11 received two units. Neutrophil engraftment after UCBT2 was observed in 10 of 15 patients at a median of 30 days (range, 13-35). The median survival for the entire cohort was 272 days (range 40–2130); one year overall survival was 36%. Engraftment and overall survival were not statistically different between those receiving 1 or 2 UCB units for UCBT2. Overall survival was not statistically different between patients who underwent UCBT2 and those who had autologous recovery or backup autologous infusions without further salvage. The proportion of patients in remission was similar in the 2 subgroups (UCBT2, 53%; autologous recovery, 50%). Relapse occurred in 2/15 patients who underwent UCBT2 and 8/10 patients who had autologous recovery or backup infusions. Forty months after transplantation, the cumulative incidence of relapse was 92% after autologous recovery vs. 50% after UCBT2 (Figure). Non–relapse mortality after UCBT2 was 73%. Conclusion Engraftment failure after UCBT frequently has no identifiable cause, and is associated with high morbidity and mortality. UCBT2 is feasible and can result in engraftment in the majority of patients, but is limited by patient condition after transplant as well as the availability of compatible grafts. UCBT2 is associated with significantly better disease control than continued autologous hematopoiesis, but additional efforts are necessary to reduce the high risk of non-relapse mortality in this group of patients. Disclosures: Hill: Celgene: Honoraria, Research Funding.

Description: Introduction: Primary CNS Lymphoma (PCNSL) is a rare and aggressive NHL associated with poor prognosis. Age, performance status, serum LDH and monocytosis at diagnosis as well as tumor location are reported to be associated with outcomes. We conducted a retrospective review of PCNSL patients to evaluate outcomes and the influence of known prognostic factors. Methods: Patients diagnosed with PCNSL between 06/2006 and 06/2014 at University Hospitals Seidman Cancer Center (Cleveland, OH) were eligible. Five patients that did not receive treatment because of very poor performance status or significant comorbidities were included. Treatment regimens included high dose methotrexate (HD-MTX) based regimens (DeAngelis LM, et al J Clin Oncol 20: 4643-8, 2002; and Ferreri AJ, et al. Lancet 374(9700):1512-20, 2009) and temozolomide plus rituximab (Wong ET, et al. Cancer 101: 139-45, 2004). In patients younger than 60 years, whole brain radiation therapy (WBRT) was administered based on patient and physician preference. Overall survival (OS) and progression free survival (PFS) were calculated from date of diagnosis to death or progression, respectively. Survival outcomes were analyzed with the Kaplan Meier method and compared between groups using the log-rank test. Results: Thirty patients were included. Patient characteristics are summarized in table 1. Median age at diagnosis was 64.5 (18-82) years. None of these patients had received a prior solid organ transplant or had prior diagnosis of lymphoma. One patient had HIV infection diagnosed at the time of PCNSL diagnosis. Lymphoma subtype was predominantly diffuse large B cell lymphoma (n=25; 83%). High-dose methotrexate (HD-MTX)-containing regimens (with or without high dose cytarabine) were used in 20 patients (66.6%). After a median follow-up of 16 months, estimated 2-year overall survival (OS) for all patients was 66.4%. Patients ineligible to receive any treatment had dismal OS (median 1.5 months), significantly inferior than patients who received any type of treatment (p 〈 0.0001). Two year OS for patients receiving treatment was 77%; there was no difference in OS among patients treated with different treatment regimens. Rituximab was not associated with longer OS. Two year PFS for patients treated with HD-MTX containing regimens was 85.7% vs. 37.5% for patients treated without HD-MTX (p=0.08). Use of WBRT was not associated with prolonged OS or PFS. On univariate analysis, elevated CSF protein was associated with inferior OS (p = 0.03); age, ECOG performance status, serum LDH at diagnosis, tumor location within the CNS, neutrophil and lymphocyte count at diagnosis and monocyte counts did not predict for OS or PFS. Among patients receiving HD-MTX based regimens 6/20 (30%) had a venous thromboembolic (VTE) episode, all occurred during HD-MTX based regimens; median time from diagnosis to VTE was 70 days (range 24 – 154), and occurred after a median of 2 cycles of chemotherapy (range 1 – 5). Conclusions: Treatment of PCNSL can result in improved outcomes and prolonged survival. Patients treated with lower intensity treatments such as temozolomide and rituximab have better OS than those not capable of tolerating even these therapies. We observed a high incidence of VTE in patients receiving HD-MTX treatment for PCNSL. The risk factors for this complication include frequent hospitalizations, use of central venous catheters and decreased mobility. Close monitoring and surveillance should be done and prophylactic measures to prevent VTE should be considered. A larger case – control study is planned to identify the specific risk factors for VTE compared with other CNS neoplasms and non – PCNSL lymphomas. Table 1.Baseline patient charachteristicsVariablePatient Number (%)Gender (Male / Female)22/8Median Age (Range)64.5 (18-82) yearsLymphoma subtype DLBCL MZL T cell lymphoma Unclassifiable25 (83.3%) 2 (6.6%) 1 (3.3%) 2 (6.6%)PCNSL location in CNS Cortex Deep brain Structures13 (43.3%) 17 (56.6%)CSF involvement9 (30%)Elevated protein in CSF14 (46.6%)Elevated serum LDH8/30 (26.6%)ECOG performance status at diagnosis 0 1 2 3 47 (23.3%) 15 (50%) 5 (16.6%) 1 (3.3%) 2 (6.6%)Age 〉 60 years21 (70%)Elevated WBC (〉10,000/mcl) at diagnosis13 (43.3%)Hemoglobin (

Description: Background: Methoxyamine (TRC-102) is a first in class inhibitor of base excision repair (BER). It covalently binds to the DNA abasic site generated by DNA-glycosylase-mediated removal of incorporated fludarabine. In vitro and animal studies demonstrated that methoxyamine augments the cytotoxicity of fludarabine against CLL cells but not normal bone marrow cells. We conducted a phase I trial to determine the maximum tolerated dose and dose limiting toxicities (DLT) of methoxyamine combined with fludarabine. Methods: Eligible patients were older than 18 years of age and had relapsed /refractory lymphoid malignancies (CLL, Lymphoma, Multiple Myeloma). Fludarabine 25mg/m2 was given intravenously daily for 5 days; methoxyamine was given intravenously on day 2 of cycle 1 and day 1 of subsequent cycles, at doses of 15, 30, 60, 90 and 120mg/m2 in a 3+3 dose escalation design. Treatment cycles were repeated every 28 days. DNA damage was assessed with the Comet Tail Length in the single cell Comet electrophoresis assay; for pharmacokinetic analysis, serum methoxyamine concentrations were measured using electrospray-ionization mass spectrometry. Results: 19 patients were enrolled in the trial; median age was 64 (range 45 – 82) years. The diagnoses included CLL (n = 10), non-Hodgkin lymphoma (NHL) (n = 7), and plasma cell myeloma (PCM) (n = 2). Median number of prior therapies was 3 (range 1 to 5). Among patients with CLL, 8/10 had received prior fludarabine therapy. No DLTs have been observed. The median number of treatment cycles administered was 3 (range 1 – 6). Grade 3 – 4 hematologic adverse events (AE) were common [neutropenia (63.1%); lymphopenia (68.4%); anemia (42.1%); thrombocytopenia (26.3%)]. Non-hematologic grade 3 – 4 events included 3 cases of pneumonia (15.8%) and one case of hyperuricemia (5.2%). Grade 1 – 2 events included fatigue (84.2%), nausea (68.4%), hypocalcemia (57.9%), anorexia (52.6%) and constipation (47.4%). Seven patients developed progressive disease (NHL = 4, PCM = 2, CLL = 1). Partial response was observed in 2 CLL patients and one case of follicular lymphoma, while 9 subjects had stable disease (CLL = 7; NHL = 2). After a median follow up of 13 months, overall survival was 75% (95% CI, 45% - 90%). Median time to next treatment among responding patients was 12 months (range 3.8 – 30.4 months). Among CLL patients, the median decrease in absolute lymphocyte count (ALC) after the first week of treatment was 90% (95% CI, 78% - 98%) and 8/10 CLL patients had normal or low lymphocyte counts. The decrease in ALC correlated directly with DNA damage measured by Comet assay 24 hours after methoxyamine infusion (Pearson Correlation 0.9162; R2 0.8995; p = 0.001). The serum half-life of methoxyamine was not affected by dosing or fludarabine co-administration. Median half-life was 41.26 hours (95% CI, 35.77 – 49.50h). Conclusions: The combination of methoxyamine and fludarabine was well tolerated, with no dose limiting toxicities observed. The combination has activity in low-grade lymphoma as well as CLL patients who relapsed after fludarabine – containing regimens. DNA damage measurements with the Comet assay correlate with disease response in CLL patients. Fludarabine remains an important component in the treatment of lymphoid malignancies. The combination with methoxyamine has the potential of increasing its activity with limited additional toxicity. Future studies are planned investigating the efficacy of fludarabine and methoxyamine combined with targeted agents for treatment of lymphoid malignancies. Disclosures Gerson: Tracon Pharmaceuticals: License of Methoxyamine Patent Patents & Royalties.

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:.