- Email: [email protected]
Members of the Intestinal Microbiota Are Associated with Relapse after Allogeneic Hematopoietic Stem Cell Transplantation
Abstracts / Biol Blood Marrow Transplant 22 (2016) S19eS481
Cox regression analyses controlling for significant confounders. Results: We included 1116 (15%) patients with pre-HCT depression and 6317 (85%) patients without pre-HCT depression transplanted between 2008 and 2012. Patients with pre-HCT depression were similar to those without pre-HCT depression with regards to age, disease distribution, disease risk index, time from diagnosis to transplant, conditioning regimen, receipt of total body irradiation, graft type, donor type, and stem cell source, but they were more likely to be female, white, divorced, less educated, not working full-time, and had lower performance status and higher number of comorbid conditions. In multivariable analyses, pre-HCT depression was associated with higher overall mortality (HR 1.13, 95% CI 1.04-1.23, p ¼ 0.004) and higher risk of grade II-IV acute GVHD (HR 1.25, 95%CI 1.141.37, p < 0.0001), but similar risk of chronic GVHD (HR 1.06, 95% CI 0.96-1.16, p ¼ 0.26). Pre-HCT depression was associated with fewer days alive and out-of-the hospital during the first 100 days (Means Ratio (MR) ¼ 0.97, 95% CI 0.95-0.99, P ¼ 0.004). Conclusion: Pre-HCT depression was associated with higher mortality, fewer days out of the hospital in the first 100 days, and higher risk of acute GVHD among allogeneic HCT recipients. Therefore patients with pre-HCT depression represent a highly vulnerable population at risk for posttransplant mortality and complications, and they may benefit from more intensive medical and psychological interventions.
5 Brincidofovir for Prevention of Cytomegalovirus (CMV) after Allogeneic Hematopoietic Cell Transplantation (HCT) in CMV-Seropositive Patients: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 3 Trial Francisco M. Marty 1, 2, Drew J. Winston 3, Roy F. Chemaly 4, Michael J. Boeckh 5, Kathlene M. Mullane 6, Tsiporah B. Shore 7, Genovefa A. Papanicolaou 8, Marion E. Morrison9, Thomas M. Brundage 9, Hervé Mommeja-Marin 9. 1 Infectious Diseases, Dana-Farber Cancer Institute, Boston, MA; 2 Brigham and Women’s Hospital, Boston, MA; 3 UCLA Medical Center– Dept.of Medicine, Los Angeles, CA; 4 Department of Infectious Diseases, Infection Control & Employee Health, UT MD Anderson Cancer Center, Houston, TX; 5 Fred Hutchinson Cancer Research Center, Seattle, WA; 6 University of Chicago, Chicago, IL; 7 Cornell Medical Center Hematology/Oncology, The New York Hospital, New York, NY; 8 Department of Medicine, Infectious Disease Service, Memorial Sloan Kettering Cancer Center, New York, NY; 9 Chimerix, Inc., Durham, NC Background: CMV is the most common viral infection after HCT. Due to hematologic and renal toxicities, current antivirals are used preemptively after evidence of CMV replication; no drug is approved for CMV prophylaxis post-HCT. Brincidofovir (BCV, CMX001) is an orally bioavailable lipid conjugate of cidofovir with in vitro activity against common transplant-related human dsDNA viruses. In a Phase 2 trial, BCV 100 mg twice weekly (BIW) prevented CMV reactivation and was generally well tolerated.
S23
Methods: The Phase 3 SUPPRESS trial (NCT01769170) compared BCV prophylaxis versus placebo through the first 14 weeks (100 days) post-HCT. Adult CMV-seropositive HCT recipients without CMV viremia at screening were randomized 2:1 to receive BCV 100 mg BIW or placebo as soon as they could swallow tablets. Randomization was stratified by center and patient risk for clinically significant CMV reactivation. Patients were assessed weekly until Week 15 post-HCT (and every 3 weeks thereafter) for CMV viremia (Roche CobasÒ PCR Assay), CMV disease, GVHD, and other adverse events. Patients who developed CMV reactivation based on pre-defined, risk-based thresholds discontinued study drug and received institutional standard of care CMV therapy. The primary endpoint of the study, assessed at Week 24 post-HCT, is the intention-to-treat incidence of CMV disease or CMV reactivation requiring preemptive therapy. CMV disease and GVHD were adjudicated by blinded committees. Results: From Aug 2013 until Jun 2015, 458 patients from 37 centers in the US, Canada, and Europe were randomized: 58% were males, 83% were white, and median age was 56 years (range, 18-77). Patients began study drug at a median of 15 days (range, 2-33) post-HCT. The indication for transplant was AML in 42% and MDS in 16%; 55% underwent myeloablative conditioning, 78% received PBSCs, 14% received BM, and 12% received cord blood or haploidentical grafts. 46% of donors were HLA-matched unrelated, 21% of donors were HLA-mismatched and 53% of donors were CMV-seropositive. Ex vivo T-cell depletion was used in 12% of patients, 29% of patients received ATG and 9% received alemtuzumab during conditioning. Thirty-eight percent of patients had ANC < 500/L at the time of first dose. In addition to CMV seropositivity, 73% had factors (T-cell depletion, cord or haplo; steroids >1mg/kg) that confer high risk for progression to CMV disease. The last study visit is expected in November 2015. Conclusion: Most patients in the SUPPRESS trial had baseline factors that place them at high risk for reactivation of CMV and progression to clinically significant disease caused by CMV and other dsDNA viruses. The SUPPRESS trial was designed to evaluate the safety and extent to which brincidofovir prophylaxis may prevent the reactivation of CMV and other prevalent dsDNA viruses that affect morbidity and mortality in HCT recipients. Final study results will be presented at the meeting.
6 Members of the Intestinal Microbiota Are Associated with Relapse after Allogeneic Hematopoietic Stem Cell Transplantation Jonathan U. Peled 1, Lilan Ling2, Eric Littman2, Satyajit Kosuri 1, Molly Maloy 1, Sergio A. Giralt 1, Juliet N. Barker 1, Miguel-Angel Perales 1, Ying Taur 3, Eric G. Pamer 4, Marcel R.M. van den Brink 1, Robert Jenq 1. 1 Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY; 2 Memorial Sloan Kettering Cancer Center, New York, NY; 3 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; 4 Infectious Diseases, Memorial Sloan-Kettering Cancer Center, New York, NY
S24
Abstracts / Biol Blood Marrow Transplant 22 (2016) S19eS481
The major causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are relapse, graft-versus-host disease (GVHD), and infection. We have previously reported that changes in the intestinal flora can affect GVHD, bacteremia, and overall survival. As intestinal bacteria are potent modulators of systemic immune responses, and since GVHD is correlated with graft-versustumor activity, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HSCT. We performed a retrospective observational analysis of 160 patients (described in Figure a) who received unmodified (T-cell-replete) allografts. The patients had been prospectively enrolled in a fecal biospecimencollection protocol. A census of the bacterial species in stool samples from the first three weeks following allHSCT was generated by 16S rRNA deep-sequencing. The area under the curve of bacterial abundance over time was used as a measure of each patientÕs cumulative exposure to each bacterial taxon. Bacterial taxa of each patient present at a frequency >1% were evaluated for association with the outcome of relapse or progression of disease within the first year after allo-HSCT in univariate Cox models. Figure b depicts hazard ratios and p values for candidate taxa (horizontal axis: larger hazard ratios are associated with more relapse. Vertical axis: statistical significance). Among
the taxa most significantly associated with freedom from relapse were several members of the human oral flora including Eubacterium limosum (HR 0.85, 95% CI (0.77- 0.95), p ¼ 0.002). We also identified bacteria associated with increased risk of relapse, such as Enterococcus faecium (HR1.25, 95% CI (1.05 e 1.48, p ¼ 0.004). In this analysis there was no formal adjustment for multiple comparisons; these data are now being validated in an additional cohort of patients. Eubacterium limosum abundance was associated with less relapse in a multivariate model adjusted for Refined Disease Risk Index (RDRI), conditioning intensity, and graft source (HR 0.85, p ¼ 0.003). Enterococcus abundance was associated with more relapse in a similar multivariate model adjusted for graft source and conditioning intensity (HR 1.2, p ¼ 0.029). After stratifying the patients by median bacterial abundance, we found that those with higher abundance of Eubacterium limosum had less relapse after transplantation (Figure c, p ¼ 0.001). Patients with high abundance of Enterococcus faecium had more relapse (Figure d, p ¼ 0.01). Thus, the results of this retrospective analysis have identified an association between relapse after allo-HSCT and the abundance of several bacteria in the intestinal flora. These might serve as potential novel diagnostics or therapeutic targets to prevent relapse and improve overall survival after allo-HSCT.
Cox regression analyses controlling for significant confounders. Results: We included 1116 (15%) patients with pre-HCT depression and 6317 (85%) patients without pre-HCT depression transplanted between 2008 and 2012. Patients with pre-HCT depression were similar to those without pre-HCT depression with regards to age, disease distribution, disease risk index, time from diagnosis to transplant, conditioning regimen, receipt of total body irradiation, graft type, donor type, and stem cell source, but they were more likely to be female, white, divorced, less educated, not working full-time, and had lower performance status and higher number of comorbid conditions. In multivariable analyses, pre-HCT depression was associated with higher overall mortality (HR 1.13, 95% CI 1.04-1.23, p ¼ 0.004) and higher risk of grade II-IV acute GVHD (HR 1.25, 95%CI 1.141.37, p < 0.0001), but similar risk of chronic GVHD (HR 1.06, 95% CI 0.96-1.16, p ¼ 0.26). Pre-HCT depression was associated with fewer days alive and out-of-the hospital during the first 100 days (Means Ratio (MR) ¼ 0.97, 95% CI 0.95-0.99, P ¼ 0.004). Conclusion: Pre-HCT depression was associated with higher mortality, fewer days out of the hospital in the first 100 days, and higher risk of acute GVHD among allogeneic HCT recipients. Therefore patients with pre-HCT depression represent a highly vulnerable population at risk for posttransplant mortality and complications, and they may benefit from more intensive medical and psychological interventions.
5 Brincidofovir for Prevention of Cytomegalovirus (CMV) after Allogeneic Hematopoietic Cell Transplantation (HCT) in CMV-Seropositive Patients: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 3 Trial Francisco M. Marty 1, 2, Drew J. Winston 3, Roy F. Chemaly 4, Michael J. Boeckh 5, Kathlene M. Mullane 6, Tsiporah B. Shore 7, Genovefa A. Papanicolaou 8, Marion E. Morrison9, Thomas M. Brundage 9, Hervé Mommeja-Marin 9. 1 Infectious Diseases, Dana-Farber Cancer Institute, Boston, MA; 2 Brigham and Women’s Hospital, Boston, MA; 3 UCLA Medical Center– Dept.of Medicine, Los Angeles, CA; 4 Department of Infectious Diseases, Infection Control & Employee Health, UT MD Anderson Cancer Center, Houston, TX; 5 Fred Hutchinson Cancer Research Center, Seattle, WA; 6 University of Chicago, Chicago, IL; 7 Cornell Medical Center Hematology/Oncology, The New York Hospital, New York, NY; 8 Department of Medicine, Infectious Disease Service, Memorial Sloan Kettering Cancer Center, New York, NY; 9 Chimerix, Inc., Durham, NC Background: CMV is the most common viral infection after HCT. Due to hematologic and renal toxicities, current antivirals are used preemptively after evidence of CMV replication; no drug is approved for CMV prophylaxis post-HCT. Brincidofovir (BCV, CMX001) is an orally bioavailable lipid conjugate of cidofovir with in vitro activity against common transplant-related human dsDNA viruses. In a Phase 2 trial, BCV 100 mg twice weekly (BIW) prevented CMV reactivation and was generally well tolerated.
S23
Methods: The Phase 3 SUPPRESS trial (NCT01769170) compared BCV prophylaxis versus placebo through the first 14 weeks (100 days) post-HCT. Adult CMV-seropositive HCT recipients without CMV viremia at screening were randomized 2:1 to receive BCV 100 mg BIW or placebo as soon as they could swallow tablets. Randomization was stratified by center and patient risk for clinically significant CMV reactivation. Patients were assessed weekly until Week 15 post-HCT (and every 3 weeks thereafter) for CMV viremia (Roche CobasÒ PCR Assay), CMV disease, GVHD, and other adverse events. Patients who developed CMV reactivation based on pre-defined, risk-based thresholds discontinued study drug and received institutional standard of care CMV therapy. The primary endpoint of the study, assessed at Week 24 post-HCT, is the intention-to-treat incidence of CMV disease or CMV reactivation requiring preemptive therapy. CMV disease and GVHD were adjudicated by blinded committees. Results: From Aug 2013 until Jun 2015, 458 patients from 37 centers in the US, Canada, and Europe were randomized: 58% were males, 83% were white, and median age was 56 years (range, 18-77). Patients began study drug at a median of 15 days (range, 2-33) post-HCT. The indication for transplant was AML in 42% and MDS in 16%; 55% underwent myeloablative conditioning, 78% received PBSCs, 14% received BM, and 12% received cord blood or haploidentical grafts. 46% of donors were HLA-matched unrelated, 21% of donors were HLA-mismatched and 53% of donors were CMV-seropositive. Ex vivo T-cell depletion was used in 12% of patients, 29% of patients received ATG and 9% received alemtuzumab during conditioning. Thirty-eight percent of patients had ANC < 500/L at the time of first dose. In addition to CMV seropositivity, 73% had factors (T-cell depletion, cord or haplo; steroids >1mg/kg) that confer high risk for progression to CMV disease. The last study visit is expected in November 2015. Conclusion: Most patients in the SUPPRESS trial had baseline factors that place them at high risk for reactivation of CMV and progression to clinically significant disease caused by CMV and other dsDNA viruses. The SUPPRESS trial was designed to evaluate the safety and extent to which brincidofovir prophylaxis may prevent the reactivation of CMV and other prevalent dsDNA viruses that affect morbidity and mortality in HCT recipients. Final study results will be presented at the meeting.
6 Members of the Intestinal Microbiota Are Associated with Relapse after Allogeneic Hematopoietic Stem Cell Transplantation Jonathan U. Peled 1, Lilan Ling2, Eric Littman2, Satyajit Kosuri 1, Molly Maloy 1, Sergio A. Giralt 1, Juliet N. Barker 1, Miguel-Angel Perales 1, Ying Taur 3, Eric G. Pamer 4, Marcel R.M. van den Brink 1, Robert Jenq 1. 1 Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY; 2 Memorial Sloan Kettering Cancer Center, New York, NY; 3 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; 4 Infectious Diseases, Memorial Sloan-Kettering Cancer Center, New York, NY
S24
Abstracts / Biol Blood Marrow Transplant 22 (2016) S19eS481
The major causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are relapse, graft-versus-host disease (GVHD), and infection. We have previously reported that changes in the intestinal flora can affect GVHD, bacteremia, and overall survival. As intestinal bacteria are potent modulators of systemic immune responses, and since GVHD is correlated with graft-versustumor activity, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HSCT. We performed a retrospective observational analysis of 160 patients (described in Figure a) who received unmodified (T-cell-replete) allografts. The patients had been prospectively enrolled in a fecal biospecimencollection protocol. A census of the bacterial species in stool samples from the first three weeks following allHSCT was generated by 16S rRNA deep-sequencing. The area under the curve of bacterial abundance over time was used as a measure of each patientÕs cumulative exposure to each bacterial taxon. Bacterial taxa of each patient present at a frequency >1% were evaluated for association with the outcome of relapse or progression of disease within the first year after allo-HSCT in univariate Cox models. Figure b depicts hazard ratios and p values for candidate taxa (horizontal axis: larger hazard ratios are associated with more relapse. Vertical axis: statistical significance). Among
the taxa most significantly associated with freedom from relapse were several members of the human oral flora including Eubacterium limosum (HR 0.85, 95% CI (0.77- 0.95), p ¼ 0.002). We also identified bacteria associated with increased risk of relapse, such as Enterococcus faecium (HR1.25, 95% CI (1.05 e 1.48, p ¼ 0.004). In this analysis there was no formal adjustment for multiple comparisons; these data are now being validated in an additional cohort of patients. Eubacterium limosum abundance was associated with less relapse in a multivariate model adjusted for Refined Disease Risk Index (RDRI), conditioning intensity, and graft source (HR 0.85, p ¼ 0.003). Enterococcus abundance was associated with more relapse in a similar multivariate model adjusted for graft source and conditioning intensity (HR 1.2, p ¼ 0.029). After stratifying the patients by median bacterial abundance, we found that those with higher abundance of Eubacterium limosum had less relapse after transplantation (Figure c, p ¼ 0.001). Patients with high abundance of Enterococcus faecium had more relapse (Figure d, p ¼ 0.01). Thus, the results of this retrospective analysis have identified an association between relapse after allo-HSCT and the abundance of several bacteria in the intestinal flora. These might serve as potential novel diagnostics or therapeutic targets to prevent relapse and improve overall survival after allo-HSCT.