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The clinical advantage of pharmacokinetic (PK)-directed-based dosing on intravenous (i.v.) versus oral busulfan-related toxicity and survival remains unclear. We performed a retrospective cohort study of sequential cohorts of patients comparing PK-directed oral and i.v. busulfan-based conditioning regimens in lymphoma patients undergoing autologous hematopoietic cell transplantation (ASCT). Patients received oral (n = 95), every 6 hours i.v. (IV16, n = 113), or once-daily i.v. (IV4, n = 86) busulfan, cyclophosphamide, and etoposide. PK-directed dosing was performed to achieve a predefined target area under the curve (AUC) of 20,000 μM-min (range: 18,400-21,600 μM-min). PK-directed dose adjustments markedly reduced the number of patients in the oral group with total AUC higher than the targeted AUC range, and reduced the variations of total AUC values in all patient groups. One hundred-day mortality was 2.1%, 3.6%, and 3.5% for oral, IV16, and IV4 cohorts, respectively. Five-year overall survival (OS) was 57% (95% confidence interval [CI] 45%-66%) and 64% (95% CI 53%-73%) for patients who received oral and i.v. busulfan, respectively. Both multivariable and instrumental variable analyses indicated the route of delivery had no significant impact on OS, whereas refractory disease and age ≥55 were significantly associated with poorer OS. In lymphoma patients undergoing ASCT, PK-directed i.v. or oral busulfan-based conditioning regimens have comparable toxicity and OS.

Background For Hodgkin lymphoma (HL) patients with refractory or relapsed (R/R) disease after primary therapy, the standard of care is a salvage regimen followed by autologous stem cell transplant (ASCT). However, patients who fail to respond to a salvage regimen have limited options. Our phase I study of cytarabine combined with fixed doses of vinorelbine, paclitaxel, etoposide, and cisplatin (VTEPA) for patients with R/R lymphoma showed an overall response rate (ORR) of 33%. Patients and Methods To further examine the effectiveness of VTEPA, we conducted a retrospective review of 30 cases of R/R HL who received a salvage combination of VTEPA. Results This population included 15 men (50%), 18 stage III/IV (60%), and 14 with an International Prognostic Score ≥3 (47%). The median number of previous regimens was 2 (range, 1-4), 19 patients (63%) received previous salvage therapy with ifosfamide, carboplatin, and etoposide. Twenty-seven patients were evaluable for response. The most common Grade 3/4 toxicities were pancytopenia (19 patients, 97%), nausea/vomiting (17, 57%), fatigue (14, 47%), and infection (6, 20%). Of the 27 patients evaluable for response, the ORR was 70% (7 complete response and 12 partial response). Twenty patients (66%) went on to ASCT and 1 patient underwent allogeneic transplant. With a median follow-up of 32 months, the median progression-free survival (PFS) and overall survival (OS) in patients who received transplantation after VTEPA were 28 and 38 months, respectively. Conclusion Treatment with VTEPA for R/R HL is feasible with manageable side effects. With a high ORR, the PFS and OS for this group of patients suggest that VTEPA is a promising regimen for HL patients in whom previous lines of therapy have failed.

Management of relapsed lymphoma depends upon the variables of chemosensitive disease and successful stem cell mobilization. The microtubule specific agents, paclitaxel and vinorelbine, have efficacy in relapsed lymphoma and can enhance stem cell mobilization. We performed a phase I dose-escalation study of cytarabine combined with fixed doses of vinorelbine, paclitaxel, etoposide and cisplatin (VTEPA) for patients with relapsed/refractory lymphoma. The regimen consisted of paclitaxel 175 mg/m2 and vinorelbine 30 mg/m2 on day 1; cisplatin 20 mg/m2 and etoposide 100 mg/m2 over 4 h on days 2 - 5. Cytarabine 2 g m/m2 over 4 h, in successive cohorts on 1, 2, or 3 consecutive days: cohort A day 5; cohort B days 4 - 5; and cohort C days 3 - 5. Sixteen patients (Hodgkin's disease, n = 6; non-Hodgkin's lymphoma, n = 10) were enrolled. Fourteen of 16 patients (88%) had refractory and seven patients (44%) had primary refractory disease. Major toxicities included hematologic toxicity, mucositis and infectious complications. Infectious complications (10/16 patients) included neutropenic fever, sepsis and fungal pneumonia. Dose-limiting toxicity was achieved in cohort C, which received three doses of cytarabine. There were 33% partial responses, 27% stable disease and 40% progressive disease following a single cycle of VTEPA. Two of 16 patients suffered treatment-related mortality. Five patients went on to receive autologous (n = 4) or allogeneic transplant (n = 1), and five out of seven patients in this heavily pretreated group who received VTEPA for mobilization of an autologous graft were successfully collected. The recommended dose of cytarabine for further evaluation in a phase II study is 2 g m/m2 for 2 consecutive days in combination with VTEPA. Treatment of subjects with relapsed/refractory lymphoma using VTEPA as second- or third-line salvage therapy produced remissions in some patients and permitted collection of grafts and subsequent autologous transplantation, supporting a planned phase II trial.

Abstract 1628 Introduction: Historically, relapsed DLBCL and HL has been associated with a high cure rate with salvage regimens followed by high dose chemotherapy and stem cell transplant (ASCT). However, patients (pts) who relapse early following upfront chemotherapy and pts who fail to respond to salvage have a poor overall response rate (ORR) with additional salvage regimens and a poor prognosis even when consolidated with ASCT (von Tresckow & Engert, 2011; Gisselbrecht et al., 2010). At present there is no standard therapy in the third-line setting for pts with DLBCL and HL. We designed a regimen: vinorelbine (30mg/m2) & paclitaxel (175mg/m2) given on day 1; etoposide (100mg/m2) & cisplatin (20mg/m2) given on days 2–5; and cytarabine (2000mg/m2) on days 4 and 5 (VTEPA) for treatment of lymphoma pts with 1° refractory disease or relapse following salvage. In phase 1, VTEPA was safe with a 33% ORR following 1 cycle (Lonial et al, 2006). Design and Methods: To examine the effectiveness of VTEPA, we conducted an IRB approved retrospective review of consecutive cases of relapsed/refractory DLBCL and HL identified from our database from 1999–2011. All pts had evidence of primary refractory disease or stable or progressive disease following first line salvage therapy. Responses following salvage VTEPA were retrospectively assessed using International Working Group Criteria (JCO 1999) for all pts. Responding pts proceeded to ASCT. Survival curves were constructed using the Kaplan-Meier method and compared with the log-rank test. Results: 74 pts (44 DLBCL and 30 HL) with a median age at diagnosis of 30 years (range 18–63) for HL and 49 years (range 20–68) for DLBCL were included. 67% of HL pts had primary refractory disease and 33% of pts had relapsed disease; 60% were stage III/IV at diagnosis. 75% of DLBCL pts had primary refractory disease and 25% of pts had relapsed disease; 73% stage III/IV. Pts received a median of 2 prior therapies (range 1–4). 63% pts with HL received prior salvage therapy with ifosfamide, carboplatin, and etoposide (ICE) and 13% with other regimens. 16 pts with HL received 1 cycle of VTEPA, 13 received 2 cycles and 1 pt received 3 cycles of VTEPA. 70% pts with DLBCL had received prior salvage therapy with rituximab (R) + ICE and 16% received other salvage regimens. 32 pts with DLBCL received 1 cycle of R-VTEPA and 12 pts received 2 cycles. The most common reported grade 3/4 toxicities were pancytopenia (97%), nausea/vomiting (58%), fatigue (30%), infectious complications (26%), diarrhea (24%), electrolyte imbalance (19%), and mucositis (16%). 70 pts (43 DLBCL and 27 HL) were evaluable for response. The ORR for DLBCL pts was 44% (9% CR and 35% PR) while that for HL pts was 70% (26% CR and 44% PR, p=0.04). 4 DLBCL pts had treatment related mortality. 34 pts went on to collect ≥2 × 106 CD34+ cells/kg; 3 pts had inadequate stem cell collection. In 23 pts collection was not attempted, and 14 pts collected stem cells prior to R+/−VTEPA. 37 pts (47%) went onto planned ASCT, and 4 pts underwent allogeneic transplantation. The PFS at 2 years for pts with HL was 68% vs. 49% for pts with DLBCL (p Conclusions: Treatment with VTEPA for heavily pretreated relapsed/refractory HL and DLBCL pts is feasible with manageable side effects, a high ORR, and permits transplantation for nearly ½ of pts. Nevertheless, outcomes for pts with refractory DLBCL is exceedingly poor compared to refractory pts with HL treated with the same approach. While there remains a great need for novel agents to aid DLBCL pts who are chemotherapy and R refractory, the favorable PFS and OS for relapsed/refractory HL pts suggest VTEPA is a promising salvage regimen for this disease. Disclosures: Sinha: Celgene: Research Funding. Kaufman:Millenium; Onxy; Novartis; Keryx: Research Funding; Merk, Celgene: Research Funding. Flowers:Spectrum: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Celgene: Consultancy; Genentech/Roche (unpaid): Consultancy; Novartis: Research Funding; Seattle Genetics: Consultancy.

Abstract 1359 Background: Improved survival has been observed after replacing oral with intravenous (iv) busulfan in autologous stem cell transplantation (ASCT) for lymphoma conditioned with busulfan (Bu), cyclophosphamide (Cy) and etoposide (VP-16; Dean et al., Br J Hematol. 2010), but it is unknown whether PK-directed iv Bu dosing is associated with additional improvements in safety or efficacy. To address this issue we performed an IRB-approved retrospective cohort study to compare the efficacy of PK-directed oral and iv Bu in lymphoma patients undergoing ASCT from 2000–2010 at Emory University. Methods: Patients included for analysis received oral Bu (1.0mg/kg every 6 hours × 16, n=97), or iv Bu (0.9mg/kg every 6 hours × 16, n=199) followed by Cy (60mg/kg qd × 2), etoposide (10 mg/kg qd x3) and infusion of previous collected autologous stem cells. Baseline demographic, lymphoma subtype, disease status, body weight (kg), body surface area (BSA), body mass index (BMI; kg/m2), stem cell dose, and other clinical and ASCT parameters were compared for oral and iv groups. Bu area under the curve (AUC), maximum bilirubin, and overall survival (OS) were compared for oral and iv groups using Chi-squared statistics and Cox regression models. Results: Diagnosis was comparable across two treatment groups except the oral treatment group had slightly higher number of NHL (58%) than iv group (43%, p=0.04). The median age and percentage of males were 43 (range 19–66) and 45 (17-69), 67% and 62.3% for oral and iv groups, respectively. Patients who received oral and iv Bu did not differ by race, mean weight, BMI, stem cell dose and disease status. BSA was greater in the iv busulfan group (p=0.03). Pharmacokinetic-directed dosing was performed in both treatment groups with a total target AUC of 20,000μMol-min. Following the initial Bu dose, the Bu half-life (mean ± std., oral: 225.8 ± 104.4, iv: 189.4 ± 47.5; p=0.0026) and total targeted AUC (oral: 20,534 ± 2,969, iv: 19,695 ± 1,434; p=0.01) were significantly different between two treatment groups. 44% of patients in oral group (n=94) and 88% of patients in the iv group (n=178) achieved targeted AUC between 18,000-22,000μMol-min. PK-directed Bu dosing generated a narrower AUC range in the iv treatment groups compared with that in the oral groups (Figure 1). Regimen-related toxicities, including VOD, were similar between patients in the oral and iv groups, with 100-day mortality of 3% and 4%, respectively (p=NS). With a mean follow-up of 1,521 and 789 days for oral and iv Bu groups, 58% and 72% patients were alive in each group respectively (Figure 2). In multivariate Cox regression models, age (HR=1.03, CL 1.01–1.05, p=0.001) significantly influenced survival, but route of Bu administration did not. Oral and iv PK-directed Bu had 2-year OS of 77% and 92% in this cohort. Conclusion: PK-directed iv Bu improves the consistency of delivering target AUC over oral PK-directed Bu with similar survival outcomes for lymphoma patients undergoing ASCT. The narrow CI for final AUC among patients receiving PK-directed iv Bu may safely permit dose-escalation of busulfan administered as part of high-dose conditioning to improve transplant efficacy. Disclosures: Flowers: Genentech/Biogen-Idec (unpaid): Consultancy; Celgene, Intellikine: Consultancy; Millennium: Research Funding; Otsuka: Research Funding. Waller:Otsuka: Research Funding.

Introduction and Methods: Despite the development of new targeted therapies for treating AML, cytarabine (Ara-C) remains the most reliably effective agent, particularly when given in high dosage (HIDAC). The outcome of AML therapy in pts > 60 years of age remains dismal with slightly more than half of pts achieving remission, and < 15% becoming long term survivors. Elderly pts do not tolerate typical HIDAC regimens because of cerebellar and other toxicities, so we have employed a modified HIDAC regimen: Ara-C 2 gm/m2/day over 4 hours once daily on days 1–6, combined with daunorubicin 45 mg/m2 days 2,3,4 for induction. Consolidation consisted of one cycle of the same chemotherapy followed by two additional cycles of mHIDAC alone, unless the pt went on to autologous or allogeneic HPCT. We report a single institution experience with 59 consecutive pts ≥ 60 y/o (including 20 pts ≥ 70 y/o), and compare outcomes with 139 similarly treated pts < 60 y/o. Excluded were pts with antecedent MDS or chemotherapy-related AML, APL, and pts with major organ dysfunction. Results and Discussion: The CR rate for pts age ≥ 60 was 66% vs 81% for those < 60 (p=0.02). The distribution of pts into cytogenetic risk categories was similar, except for an under-representation of good risk cytogenetics among older pts (3% vs 14%, p=0.025). Overall survival for older pts was worse than that for younger individuals primarily due to an excess of early deaths, however, disease free survival among complete responders was similar for the 2 age groups (see below). There were 11 (16%) early deaths within 60 days among older pts, 4 with residual leukemia and 7 during aplasia. Early death occurred in 7 (5%) of the younger pts, 2 with residual leukemia and 5 during aplasia. There were 4 deaths (3 infectious and 1 stroke) during consolidation, 3 in the older and 1 in the younger group. There were also 2 late deaths in remission (both older pts) which were unrelated to AML or therapy. Clinically significant cerebellar toxicity was observed in 4 (6.8%) of the older pts and 3 (2%) of the younger pts, for a total of 7 episodes associated with 535 courses of Ara-C delivered (1.3%). 60% of older pts were able to complete 2 or 3 courses of consolidation therapy. Our data confirm the challenges of treating older pts with AML, but suggest that a significant subgroup can tolerate and benefit from aggressive therapy which includes dose intensification of Ara-C. This mHIDAC regimen is effective and well tolerated, and repeated administration to older pts is feasible. Overall Survival Overall Survival Relapse-Free Survival Relapse-Free Survival