- Email: [email protected]
MDS Results in Improved Outcomes Comparable to Matched Related HCT
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
S329
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)
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Abstracts / Biol Blood Marrow Transplant 22 (2016) S19eS481
Patients Characteristic
Allo-Related
Unrelated Donor
Number ( AML/MDS) Mean age ( Range ) Status at Transplant CR1 (Complete remission -1) CR2 (Complete remission -2) PIF, REL (primary refractory, Relapse) Conditioning Regimen Intensity FIC (Full Intensity)/Flu-Bu4 RIC ( Reduced Intensity)Flu-Bu2 CD34 Infused X million/Kg (Range) Mean (million/Kg) Median to WBC engraftment ( Days) Median to Plat engraftment (Days)
29 (22/7) 53.2 ( 34-73)
69 (61/8) 55.95 (26-73)
17 (59%) 3 (10%) 9 (31%)
44 (64%) 5 (7%) 20 (29%)
22 (75%) 7 (25%)
44 (64%) 25 (36%)
5.8 12.57 19.27
6.83 11.64 18
P 0.32 0.81
0.41
with Fludarabine 40 mg/m2 for 4 days and Busulfan 3.2 mg/ Kg single daily dose for 4 days or reduced intensity conditioning with Fludarabine and Busulfan 3.2 mg/Kg single daily dose for 2 days. GVHD prophylaxis for FIC was Tacrolimus/ mini Methotrexate and Tacrolimus/Mycophenolate for RIC. Thymoglobulin was added at dose of 1.5 mg/Kg for 3 days for MUD patients only. Results: With median follow of 772 days( RD 809 days, MUD 756 days), the overall survival at 1 year was 76% +/- 8% and 72% +/- 5% for RD and MUD respectively, P¼0.89. All patient engrafted except two patients in FIC MUD group (Primary graft failure). The cumulative incidence of relapse at 1 year was 38% +/- 8% and 24% +/- 5% for RD & MUD respectively, while the treatment related mortality (TRM) at 2 years were 16% +/- 3% and 20% +/- 3% for RD and MUD HCT recipients. Cumulative Incidence acute GVHD grade II-IV was 34% in RD at day 100 and day 180 while it was 28% & 38% at day 100 and day 180 in MUD respectively. The cumulative incidence of mild to moderate chronic GVHD was observed in 49% of MUD recipients and 53% of RD recipients at 2 years. Conclusion: The addition of thymoglobulin to MUD HCT results in outcomes comparable to RD HCT in AML/MDS patients. Our data suggest the use of MUD donors as second choice for patient who lacks matched siblings while reserving other alternative donors for patients who lacks full match MUD donors.
487 Comparison of Outcomes with Two Calcineurin InhibitorBased Graft-Versus-Host-Disease Prophylactic Regimens after Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies Rashmi Khanal, Valeriy Sedov, Ridhi Gupta, Mark Thomas Burbridge, Colleen Butcher, Kylie Capdevila, Kathy Hogan Edwards, Kristy Martin, Amanda Littleton, Cindy Kramer, Molly Schneider, Juan Carlos Varela, Elizabeth J. Williams, Robert Stuart, Saurabh Chhabra, Carolyn Ann Gentles. Blood and Marrow Transplant Program, Medical University of South Carolina, Charleston, SC Background: Acute Graft-versus-Host Disease (aGVHD) occurs in 35-48% allogenic hematopoietic cell transplantation (alloHCT) patients and remains a major problem to longterm survival after alloHCT, despite the use of aggressive GVHD prophylaxis. We compared the outcomes at our institution in alloHCT patients who received reduced intensity conditioning (RIC) of Fludarabine and Melphalan for alloHCT and either tacrolimus (FK)/methotrexate (MTX; days+1, +3, +6, +11) or cyclosporine (CSP)/mycophenolate mofetil (MMF) for GVHD prophylaxis.
0.075 0.93 0.39
Patients and Methods: Retrospective chart review of 55 patients who received RIC alloHCT conditioning [(Flu 25 mg/ m2 IV/d d-5 to -1) and Mel (70mg/m2 IV/d d-2 and -1)] between Jan 2012 and May 2015 was conducted. T cell depletion, second transplants, cord blood and haploidentical transplants were excluded. Forty five patients received GVHD prophylaxis with CSP/MMF and 10 received FK/MTX. Patients with AML, MDS, ALL, NHL and HL were included. All the patients had high disease risk index (DRI), most had de novo disease and few had treatment related disease, HCT-CI score ranged from 0-6. Results: Median follow-up for FK/MTX group was 9.8 months and for CSP/MMF group was 17.0 months. Survival at d100 and 6 months was 90% in the FKMTX group and 75.5% and 60% in CSP/MMF group, respectively. One-year survival in the CSP/MMF group was 48.9%. There was no GVHDrelated death in FK/MTX group whereas 53.8% (n¼26) of CSP/ MMF patients died of GVHD: 46.9% (n¼32) had Grade III-IV GVHD. Median time to neutrophil and platelet engraftment in FK/MTX group was 16.6 and 19.5 days and 14.5 and 13.6 days in CSP/MMF group, respectively. Median OS was 19.6 months in CSP/MMF group and 20.3 months in FK/MTX Table 1 Study Outcomes Regimen
FK/MTX
CSP/MMF
Number of patients Total Deaths-all cause 100 day survival 6 month survival Relapse aGVHD I-IV aGVHD III-IV aGVHD-related deaths
10 2 (20%) 9 (90%) 9 (90%) 0 2 (100%) 0 0
45 26 (57.7%) 34 (75.5%) 27 (60%) 5 (11.11%) 32 (71.1%) 15 (46.9%) 14 (53.84%)
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
S329
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)
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Abstracts / Biol Blood Marrow Transplant 22 (2016) S19eS481
Patients Characteristic
Allo-Related
Unrelated Donor
Number ( AML/MDS) Mean age ( Range ) Status at Transplant CR1 (Complete remission -1) CR2 (Complete remission -2) PIF, REL (primary refractory, Relapse) Conditioning Regimen Intensity FIC (Full Intensity)/Flu-Bu4 RIC ( Reduced Intensity)Flu-Bu2 CD34 Infused X million/Kg (Range) Mean (million/Kg) Median to WBC engraftment ( Days) Median to Plat engraftment (Days)
29 (22/7) 53.2 ( 34-73)
69 (61/8) 55.95 (26-73)
17 (59%) 3 (10%) 9 (31%)
44 (64%) 5 (7%) 20 (29%)
22 (75%) 7 (25%)
44 (64%) 25 (36%)
5.8 12.57 19.27
6.83 11.64 18
P 0.32 0.81
0.41
with Fludarabine 40 mg/m2 for 4 days and Busulfan 3.2 mg/ Kg single daily dose for 4 days or reduced intensity conditioning with Fludarabine and Busulfan 3.2 mg/Kg single daily dose for 2 days. GVHD prophylaxis for FIC was Tacrolimus/ mini Methotrexate and Tacrolimus/Mycophenolate for RIC. Thymoglobulin was added at dose of 1.5 mg/Kg for 3 days for MUD patients only. Results: With median follow of 772 days( RD 809 days, MUD 756 days), the overall survival at 1 year was 76% +/- 8% and 72% +/- 5% for RD and MUD respectively, P¼0.89. All patient engrafted except two patients in FIC MUD group (Primary graft failure). The cumulative incidence of relapse at 1 year was 38% +/- 8% and 24% +/- 5% for RD & MUD respectively, while the treatment related mortality (TRM) at 2 years were 16% +/- 3% and 20% +/- 3% for RD and MUD HCT recipients. Cumulative Incidence acute GVHD grade II-IV was 34% in RD at day 100 and day 180 while it was 28% & 38% at day 100 and day 180 in MUD respectively. The cumulative incidence of mild to moderate chronic GVHD was observed in 49% of MUD recipients and 53% of RD recipients at 2 years. Conclusion: The addition of thymoglobulin to MUD HCT results in outcomes comparable to RD HCT in AML/MDS patients. Our data suggest the use of MUD donors as second choice for patient who lacks matched siblings while reserving other alternative donors for patients who lacks full match MUD donors.
487 Comparison of Outcomes with Two Calcineurin InhibitorBased Graft-Versus-Host-Disease Prophylactic Regimens after Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies Rashmi Khanal, Valeriy Sedov, Ridhi Gupta, Mark Thomas Burbridge, Colleen Butcher, Kylie Capdevila, Kathy Hogan Edwards, Kristy Martin, Amanda Littleton, Cindy Kramer, Molly Schneider, Juan Carlos Varela, Elizabeth J. Williams, Robert Stuart, Saurabh Chhabra, Carolyn Ann Gentles. Blood and Marrow Transplant Program, Medical University of South Carolina, Charleston, SC Background: Acute Graft-versus-Host Disease (aGVHD) occurs in 35-48% allogenic hematopoietic cell transplantation (alloHCT) patients and remains a major problem to longterm survival after alloHCT, despite the use of aggressive GVHD prophylaxis. We compared the outcomes at our institution in alloHCT patients who received reduced intensity conditioning (RIC) of Fludarabine and Melphalan for alloHCT and either tacrolimus (FK)/methotrexate (MTX; days+1, +3, +6, +11) or cyclosporine (CSP)/mycophenolate mofetil (MMF) for GVHD prophylaxis.
0.075 0.93 0.39
Patients and Methods: Retrospective chart review of 55 patients who received RIC alloHCT conditioning [(Flu 25 mg/ m2 IV/d d-5 to -1) and Mel (70mg/m2 IV/d d-2 and -1)] between Jan 2012 and May 2015 was conducted. T cell depletion, second transplants, cord blood and haploidentical transplants were excluded. Forty five patients received GVHD prophylaxis with CSP/MMF and 10 received FK/MTX. Patients with AML, MDS, ALL, NHL and HL were included. All the patients had high disease risk index (DRI), most had de novo disease and few had treatment related disease, HCT-CI score ranged from 0-6. Results: Median follow-up for FK/MTX group was 9.8 months and for CSP/MMF group was 17.0 months. Survival at d100 and 6 months was 90% in the FKMTX group and 75.5% and 60% in CSP/MMF group, respectively. One-year survival in the CSP/MMF group was 48.9%. There was no GVHDrelated death in FK/MTX group whereas 53.8% (n¼26) of CSP/ MMF patients died of GVHD: 46.9% (n¼32) had Grade III-IV GVHD. Median time to neutrophil and platelet engraftment in FK/MTX group was 16.6 and 19.5 days and 14.5 and 13.6 days in CSP/MMF group, respectively. Median OS was 19.6 months in CSP/MMF group and 20.3 months in FK/MTX Table 1 Study Outcomes Regimen
FK/MTX
CSP/MMF
Number of patients Total Deaths-all cause 100 day survival 6 month survival Relapse aGVHD I-IV aGVHD III-IV aGVHD-related deaths
10 2 (20%) 9 (90%) 9 (90%) 0 2 (100%) 0 0
45 26 (57.7%) 34 (75.5%) 27 (60%) 5 (11.11%) 32 (71.1%) 15 (46.9%) 14 (53.84%)