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Abstracts / Biol Blood Marrow Transplant 22 (2016) S19eS481
Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, funded by the NCI Contract No. HHSN261200800001E.
483 Peripheral Blood Stem Cell Collection on Day 4 Is Feasible and Safe in a Majority of Allogeneic Stem Cell Transplant Donors Esha Kaul1, Sweta Kothari1, Rasika Setia2, Sanjeev Sharma1, Saad Suleiman1, Vipin Khandelwal1, Gaurav Kharya1, Bharti Sharma1, Anil Handoo3, Dharma Choudhary1. 1 Hematology-Oncology and Bone Marrow Transplant, BL Kapur Center for Bone Marrow Transplant, New Delhi, India; 2 Blood Bank and Transfusion Medicine, BL Kapur Superspeciality Hospital, New Delhi, India; 3 Hematology and Lab Sciences, BL Kapur Superspeciality Hospital, New Delhi, India Background: Peripheral blood stem cells (PBSCs) are the most common stem cell source in allogeneic stem cell transplants (ASCT). Most common protocols harvest stem cells on day 5 of G-CSF mobilization. There are limited reports of successful stem cell collection on day 4 of G-CSF. At our center, we prefer collection on day 4, and we present our data with this strategy. Methods: 79 healthy donors for ASCT who were collected between March 2014 & March 2015 were included. The donors were screened and selected in accordance with institutional guidelines. G-CSF was administered at a dose of 10mg/kg subcutaneously once daily for 4 days. Apheresis was performed on day 4 on either a Cobe or Amicus machine depending on logistics, in accordance with manufacturer’s guidelines. Target stem cell dose was 5 x 10 6 CD34+ cells /kg recipient body weight. Results: All 79 donors were related ASCTs, with 46 (58%) being male. The majority (89%) of the donors were siblings (39 brother, 31 sister). Median donor age was 34 years (4-61) and median weight was 64 kgs (11-129). 59 (75%) were fully HLA matched (6/6 or 10/10) and 20 (25%) were haploidentical. The most common indications for ASCT were acute myeloid leukemia in 22 (28%), thalassemia in 12 (15%), aplastic anemia in 12 (15%) and acute lymphoblastic leukemia in 10 (13%). Vascular access was central in 43 (54%) and peripheral in 36 (46%). Amicus and COBE systems were used in 53 (67%) and 26 (33%), respectively. Median pre-pheresis peripheral blood CD34 count on day 4 was 35.85/ml (5.49144.6). Median number of CD34+ cells collected on day 4 were 5.05 x 10 6/kg recipient body weight (0.82-118.52). A second session of apheresis was required in 11(14%) donors and median day 5 dose was 3.25 x 10 6/kg (0.02-5.4) recipient body weight. Donor/recipient weight <1 were more likely to collect less than goal with an Odds Ratio of 4.17 (95% CI 1.6-10.9, p value 0.0036). Some donors had body aches, but there were no serious adverse events. Conclusions: We present a large and successful experience with day 4 peripheral blood stem cell collection in donors of
allogeneic stem cell transplants. The relatively younger age of donors at our center may be the reason for our success with this strategy with a second day collection required in a small minority. Weight mismatch was a strong predictor of suboptimal collection. This strategy limits total G-CSF use and associated side-effects in healthy donors and could also be cost effective in a resource limited situation.
484 In Contrast to Phenytoin, Levetiracetam Does Not Increase Busulfan Clearance When Given As Anti-Seizure Prophylaxis Jitesh D. Kawedia 1, Alan L. Myers 1, Mark A. Kramer 1, Alison M. Gulbis 2, Richard E. Champlin 3, Borje S. Andersson 4, Uday R. Popat 3. 1 Pharmacy Research, Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX; 2 Division of Pharmacy, UT MD Anderson Cancer Center, Houston, TX; 3 Stem Cell Transplantation and Cellular Therapy, UT MD Anderson Cancer Center, Houston, TX; 4 Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX Background: High dose busulfan (Bu) is widely used in conditioning regimens for patients undergoing hematopoietic stem cell transplantation and shows wide inter patient pharmacokinetic (PK) variability. Influence of Bu plasma exposure on treatment outcomes and toxicities have led to the continued use of therapeutic drug monitoring of Bu. We investigated Bu PK in a unique myeloablative regimen with a goal to lower non-relapse mortality in patients with comorbidities and old age, in which IV Bu was administered daily for 6 days with a break of 7 days after the first 2 doses of Bu. Target Bu exposure (AUC) was 16,000 or 20,000 mM-min. Because seizures are a major side effect of high-dose Bu therapy, phenytoin (PHT) is commonly given as anti-seizure prophylaxis. In preliminary analysis we noted a significant increase in Bu clearance on day -6 compared to day -13. We hypothesized that this was due to PHT, an enzyme inducer, and replaced it with levetiracetam (LEV). We herein report the results of the effect of anti-seizure prophylactic agent on Bu PK. Methods: All patients received a fixed dose of IV Bu 80 mg/ m2 daily on days -13 and -12. Subsequently they received fludarabine 40 mg/m2/d x 4, followed by IV Bu x 4 (days -6 to -3). Dose of Bu on day -6 and day -4 were adjusted based on PK studies done on day -13 and day -6 respectively, to achieve a total treatment course AUC of 16,000 or 20,000 mMmin. At start of the study, PHT (600 mg orally 1st dose, then 600 mg or 300 mg if BSA <1.8 m2), and later LEV (500 mg 1st dose then 500 mg twice daily) were used for seizure prophylaxis. Results: Total of 196 patients were enrolled; of these, 147 received PHT and 49 received LEV. In the PHT arm, 49 and 98 patients received Bu target AUC of 16,000 or 20,000 mMmin respectively. Due to significant increase (15%, p ¼
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Table l Comparison of Busulfan PK parameters in the two anti-seizure prophylaxis arms Busulfan PK parameters
Phenytoin *
CL (ml/min/m2) day-13 CL (ml/min/m2) day-6 Half-life (h) day-13 Half-life (h) day-6 Change in CL (%)
96.7 111.3 2.84 2.59 15.5
*mean SD, an ¼ 146, bn ¼ 143, cn ¼ 49, CL ¼ Clearence
16.1 17.2 0.44 0.37 10.6
Levetiracetam*c a b c b b
99.2 103.8 2.7 2.7 4.9
18.3 17.3 0.48 0.45 7.4
p-value 0.6 0.019 0.1 0.3 0.00001
Abstracts / Biol Blood Marrow Transplant 22 (2016) S19eS481
Figure 1. Percent change in busulfan clearance from day -13 to day-6 in the two anti-seizure prophylaxis arms.
0.00001) in Bu clearance (CL) between day-13 and -6, PHT was replaced with LEV and Bu target AUC was maintained at 20,000 mM-min as it was well tolerated. There was no statistical difference in Bu PK parameters between 16,000 and 20,000 AUC arms (p > 0.15). Also, there was no difference in day-13 PK parameters between PHT and LEV arms (Table1). However, the day-6 CL was higher in PHT arm, (p ¼ 0.019) but no difference in half-life. Finally, the increase in Bu CL between day -13 and day -6 was 10% higher in PHT arm, (p ¼ 0.00001, Figure 1). No seizures were seen in any patient in either arm. Conclusion: PHT increases Bu CL, but LEV does not affect Bu CL, and has comparable efficacy for seizure prevention. Hence, LEV is a reasonable alternative to PHT to prevent seizures in patients receiving high dose Bu.
485 Cytomegalovirus Reactivation Does Not Reduce the Risk of Disease Relapse after Allogeneic Hematopoietic Stem Cell Transplantation Natasha Kekre 1, Haesook T. Kim 2, Vincent T. Ho 3, John Koreth 3, Philippe Armand 3, Brett Glotzbecker 3, Sarah Nikiforow 4, Edwin P. Alyea III 3, Robert J. Soiffer 5, Joseph H. Antin 6, Francisco Marty 7, Corey S. Cutler 3. 1 Hematology, The Ottawa Hospital, Ottawa, ON, Canada; 2 Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; 3 Hematologic Malignancies, DanaFarber Cancer Institute, Harvard Medical School, Boston, MA; 4 Dana-Farber Cancer Institute, Boston, MA; 5 Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA; 6 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 7 Infectious Diseases, Dana Farber Cancer Institute, Boston, MA Introduction: A protective effect against hematological disease relapse mediated by Cytomegalovirus reactivation (CMV-rt) and NK cell proliferation induced by this viremia has been proposed. We analyzed the possible link between CMV-rt and malignant disease relapse after hematopoietic stem cell transplantation (HSCT) in a large single institution cohort. Methods: We identified 1384 patients who underwent first allogeneic HSCT between 1/1/2006 and 8/31/2012 at the Dana Farber Cancer Institute. Data were extracted from the HSCT data repository and confirmed by medical chart review. All patients underwent weekly CMV surveillance in the first
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100 days after HSCT, and as clinically indicated beyond day +100. CMV-rt was defined as detection of more than 500 copies/mL of CMV DNA by quantitative real-time PCR. The median follow-up time among survivors was 48 months (range 11.5-103.2). Results: Among HSCT recipients, 746 (53.9%) were CMV seropositive prior to HSCT. 301 patients had CMV-rt after allogeneic HSCT (21.7%). Of these 301 patients, the median age was 53 (range 19-73), 52.2% were male, 39.2% had AML, and 12.6% received an umbilical cord blood HSCT. The median time to CMV-rt was 58 days (range 3-1512). The majority of CMV-rt occurred within the first 100 days after HSCT (68.4%). The cumulative incidence of CMV-rt was 21.4% (95% CI 19-24) by 2 years after HSCT, with no difference by disease category (p¼0.69). 29 patients went on to develop invasive CMV disease, with colitis (14) and pneumonitis (10) being the main sites of involvement. There was no difference in age, diagnosis, conditioning intensity, or disease risk index between patients with and without CMV-rt in univariable analysis. CMV-rt was associated with donor type, with mismatched unrelated donors having the highest risk (32.8%, p¼0.0005) and stem cell source, with cord blood recipients having the highest risk (37.3%, p¼0.0002). In multivariable Cox models stratified by conditioning intensity and treating CMV-rt as a timedependent variable, CMV-rt was associated with worse overall and progression free survival (HR¼1.37, 95% CI 1.141.64 and HR¼1.3, 95% CI 1.08-1.57 respectively) and higher non-relapse mortality (NRM HR¼1.69, 95% CI 1.28-2.23). There was no effect of CMV-rt on the cumulative incidence of relapse (HR¼1.08, 95% CI 0.84-1.39), even when restricted to AML patients only. In a day 100 landmark analysis excluding death or relapse within 100 days, the 2-year cumulative incidence of NRM was higher in patients with CMV-rt by day 100 compared to those without CMV-rt (19.3% vs. 11.5%, p¼0.01), but there was no difference in relapse (p¼0.45). Conclusion: In this large cohort of patients undergoing allogeneic HSCT for hematologic malignancy, NRM was significantly associated with CMV-rt, but not relapse. Strategies to prevent and pre-emptively treat CMV therefore remain pertinent in patients undergoing allogeneic HSCT.
486 Thymoglobulin after Matched Unrelated Hematopoietic Stem Cell Transplantation (HCT) in AML/MDS Results in Improved Outcomes Comparable to Matched Related HCT Yasser Khaled 1, Rushang D. Patel 2, Wesam Ahmed 2, Shahram Mori 3, Melhem Solh 2. 1 Blood and Marrow Transplant, University of Tennessee HSC, Memphis, TN; 2 Florida Hospital Cancer Institute, Orlando, FL; 3 Bone Marrow and Cellular Therapy, Florida Hospital Cancer Institute, Orlando, FL Background: The use of thymoglobulin after allogeneic hematopoietic stem cell transplantation (HCT) has been implicated in increased the risk of relapse and infections. Recent data have suggested the use of haplo-transplant as second choice alternative to MUD after first choice related donor (RD). We hypothesized that outcomes after MUD transplant with use of thymoglobulin similar to RD HCT would justify the use of MUD HCT with addition of thymoglobulin as best second donor choice after RD. Method: We compared the outcomes of 98 (29 matched RD/ 69 matched MUD) consecutive patients with AML/MDS who underwent HCT with Fludarabine/ Busulfan conditioning between 7/2009-12/2014. Patients Characteristics are shown in Table-1. Patients received full intensity conditioning (FIC)