ALBERT

Description: 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

Description: It has been previously reported that increases in relapse and graft rejection can be associated with a low busulfan area under the curve (AUC) and hepatic toxicities are associated with a high AUC. This has lead to strategies to adjust busulfan dosing to achieve a target AUC. A retrospective analysis was performed in patients with severe obesity, defined as a Body Mass Index (BMI) greater than 40, to evaluate the reliability of IV busulfan dosed using the package insert dosing strategy to reach a targeted AUC. The study included 11 females and 8 males who received IV busulfan as part of their hematopoietic progenitor cell transplant preparative regimen. There were 11 autologous and 8 allogeneic transplants for lymphoma (10) and leukemia (9). The mean and median ages were 38 and 41 years (range 19–51). The mean and median BMIs for this population were 47.8 and 46.2 (range 40.4–62.7). The mean and median weights were 139.5 kg and 142.5 kg (range 107–192.3). TDM was performed with the first dose of busulfan along with subsequent dosage adjustments to achieve a target AUC of 1150–1350 micromol X min/L. Busulfex package insert dosing recommendations are for 16 doses of 0.8 mg/kg (12.8 mg/kg) using an adjusted ideal body weight (AIBW) for obese patients. AIBW = 0.25 × (actual weight − ideal body weight) + ideal body weight. Using the AIBW dosing, the mean starting dose to actual body weight ratio was 0.48 mg/kg (range 0.40–0.55 mg/kg). Based on the AUC analysis, the predicted mean AUC using the AIBW dosing was 972 (range 702–1356). Six AUCs were below 900, 10 AUCs were above 900 but below 1150, 2 AUCs were within the target range and 1 AUC was greater than 1350. Thirteen of the patients had repeat AUC analyses following a subsequent dose to confirm that the dose adjustments achieved the targeted AUCs. Seven of these patients had further dose adjustments following the repeat AUC analysis. Five patients with a busulfan mean half-life of 235 minutes (range 218–247 minutes) had higher AUCs than the rest of the group. The mean and median AUCs for these 5 patients were 1177 and 1223 (range 997–1357). The remaining 14 patients with a mean busulfan half-life of 177 minutes (range 151–201) had mean and median AUCs of 899 and 903 (range 702–1105). The total therapy delivered ranged from 12.7 to 21.4 mg/kg based on the AIBW. When calculated on actual weight, the range was 6.9 to 11.24 mg/kg. Conclusion: The AIBW dosing strategy of IV busulfan is inadequate to achieve the targeted AUC of 1150–1350 in severely obese patients. Severely obese patients require dose increases in the majority of cases, while those with delayed clearance could be overdosed if higher doses are administered without TDM. Severely obese patients require TDM and the majority will require dosage adjustments to administer IV busulfan in the targeted therapeutic range.

Description: Background: Mucosal injury and concomitant associated side effects represents a major toxicity of autologous transplant for myeloma. The use of Palifermin has been demonstrated to reduce mucositis severity scores and duration in randomized trials. We sought to evaluate the effect of palifermin on overall platelet transfusion requirements as an indirect measure of reduced GI toxicity. Since palifermin has been shown to decrease mucosal damage caused by conditioning regimens for PBSCT, it was theorized that palifermin’s protective effects might lead to a reduction in the platelet transfusion requirements for these patients. Methods: Thirty six consecutive myeloma PBSCT patients conditioned with melphalan 200 mg/m2 plus palifermin (dosed per manufacturers recommendations) were retrospectively evaluated for platelet transfusion requirements following autologous transplant. As a historical control, data were retrospectively collected on thirty eight consecutive myeloma PBSCT patients conditioned with the same regimen prior to the routine use of palifermin. Platelet support consists of transfusion of leukoreduced irradiated single donor pheresis products. Platelet transfusions were dictated by standard clinical practice on the transplant service either for a routine platelet count

Description: 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

Description: 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.