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J.P. Cooper et al.
Table 2. Association of transplant era with major endpoints.
Table 3. Association of transplant era with incidences of organ compli- cations and infections.
Overall survival 1997 – 2003 2004 – 2009 2010 – 2017
Progression-free survival 1997 – 2003
2004 – 2009
2010 – 2017
Relapse/progression 1997 – 2003
2004 – 2009
2010 – 2017
Non-relapse mortality 1997 – 2003
2004 – 2009
2010 – 2017
Relapse-related mortalityb 1997 – 2003
2004 – 2009
2010 – 2017
Acute GvHD grade 2–4 1997 – 2003
2004 – 2009
2010 – 2017
Acute GvHD grade 3–4 1997 – 2003
2004 – 2009
2010 – 2017
Chronic GvHD 1997 – 2003 2004 – 2009 2010 – 2017
Adjusteda (n=1,668) HR (95% CI)
1.0
0.72 (0.6 – 0.9) 0.60 (0.5 – 0.7)
1.0
0.78 (0.7 – 0.9) 0.63 (0.5 – 0.8)
1.0
0.93 (0.8 – 1.1) 0.71 (0.6 – 0.9)
1.0
0.58 (0.5 – 0.7) 0.52 (0.4 – 0.7)
1.0
0.85 (0.7 – 1.1) 0.80 (0.6 – 1.0)
1.0
0.81 (0.7 – 1.0) 0.64 (0.5 – 0.8)
1.0
0.67 (0.5 – 1.0) 0.54 (0.4 – 0.8)
1.0
0.59 (0.5 – 0.7) 0.57 (0.5 – 0.7)
P
0.0001 <0.0001
0.002
< 0.0001
0.52 0.006
< 0.0001
< 0.0001
0.15 0.10
0.03
< 0.0001
0.03 0.004
< 0.0001
< 0.0001
Organ Toxicity (n=1,548)
Bilirubin > 4 mg/dL 1997 – 2003
2004 – 2009
2010 – 2017
Bilirubin > 10 mg/dL 1997 – 2003
2004 – 2009
2010 – 2017
Creatinine > 2x baseline 1997 – 2003
2004 – 2009
2010 – 2017
Infections (n=1,502)
Gram-negative bacteremia 1997 – 2003
2004 – 2009
2010 – 2017
Invasive fungal infection 1997 – 2003
2004 – 2009
2010 – 2017
CMV antigenemiab 1997 – 2003 2004 – 2009 2010 – 2017
CMV diseaseb 1997 – 2003 2004 – 2009 2010 – 2017
Adjusteda OR (95% CI)
1.0
0.28 (0.18 – 0.42) 0.22 (0.14 – 0.35)
1.0
0.18 (0.08 – 0.43) 0.21 (0.09 – 0.50)
1.0
0.63 (0.47 – 0.84) 0.71 (0.52 – 0.97)
HR (95% CI)
1.0
0.82 (0.70 – 0.97) 0.68 (0.56 – 0.82)
1.0
0.75 (0.63 – 0.89) 0.63 (0.52 – 0.76)
1.0
1.15 (0.94 – 1.40) 0.86 (0.69 – 1.08)
1.0
0.86 (0.70 – 1.06) 0.66 (0.52 – 0.85)
P
< 0.0001 < 0.0001
0.0001
0.0005
0.002 0.03
P
0.02 < 0.0001
0.0008
< 0.0001
0.18 0.19
0.16
0.001
HR: hazard ratio; CI: confidence interval; GvHD: graft-versus-host disease; MM: multiple myeloma; AML: acute myeloid leukemia; CMV: cytomegalovirus; R: recipient; D: donor; HCT: hematopoietic cell transplantation; HCT-CI: hematopoietic cell transplantation comorbidity index. aAdjusted for transplant center (stratification); treatment type (on- protocol, off-protocol), age (≤49, 50–59, ≥60 years); disease risk group (low, standard, high); MM diagnosis; AML diagnosis; CMV (R– and D–, R+ or D+); donor relation (relat- ed, unrelated); sex mismatch (female to male, others); prior HCT (no, yes); allele mis- match (no, yes); HCT-CI (0, 1–2, 3, ≥4, missing). Kahl disease risk groups and HCT-CI assigned as described.17,20 bRelapse-related mortality refers to survival after relapse among patients that relapsed.
reduction in NRM. Topically-active glucocorticoids such as beclomethasone dipropionate were introduced which, when given with prednisone to patients with gastroin- testinal GvHD in a randomized, placebo-controlled trial, allowed for a rapid taper of prednisone dosing starting 10 days after initiation, significantly reduced the risk of GvHD-treatment failure, and reduced the risk of mortality by 37% after a median follow-up of 3.6 years.3 Decreases in the use of systemic glucocorticoids for treatment of acute GvHD, along with the addition of sirolimus to MMF with a calcineurin inhibitor as GvHD prophylaxis have also resulted in lower rates of fungal infections2 and CMV reactivation.6,8 Changes in infection prophylaxis also likely contributed to reductions in NRM. This included a shift in antibacterial prophylaxis from cephalosporins to fluoro- quinolones during periods of neutropenia,9-11 a shift in antifungal prophylaxis from fluconazole to extended- spectrum triazoles (itraconazole, voriconazole, posacona- zole) with greater activity against mold,12,13 empirical anti-
OR: odds ratio; HR: hazard ratio; CI: confidence interval; MM: multiple myeloma; AML: acute myeloid leukemia; R: recipient; D: donor; CMV: cytomegalovirus; HCT: hematopoietic cell transplantation; HCT-CI: hematopoietic cell transplantation comor- bidity index. aAdjusted for transplantation center; treatment type (protocol, treatment plan); age (≤49, 50–59, 60+ years); disease risk group (low, standard, high); MM diagno- sis; AML diagnosis; CMV (R– and D–, R+ or D+); donor relation (related, unrelated); sex mismatch (female to male, others); prior HCT (no, yes); allele mismatch (no, yes); and HCT-CI (0, 1–2, 3, ≥4, missing). bCMV endpoints evaluated only among seropositive recipients at HCT (n = 911 for multivariate analysis).
fungal therapy for patients with pulmonary nodules,33 and the adoption of pre-emptive antiviral therapy driven by highly sensitive PCR-based CMV DNA diagnostic testing of blood samples.14-16
Reduction in the incidences of acute GvHD in our later patient cohorts were due, in part, to the increasing use of sirolimus as a component of GvHD prophylaxis for unre- lated recipients6,8 and the adoption of ursodiol to prevent cholestasis and hyperbilirubinemia.4 In addition to our data here documenting the beneficial effect of sirolimus, we recently reported the results of a randomized phase III trial showing that the addition of sirolimus to the standard prophylactic regimen of MMF and cyclosporine in unrelat- ed recipients reduced the day 100 cumulative incidence of grades 2–4 acute GvHD (26% vs. 52%), resulting in signif- icantly reduced use of steroids and markedly improved 1-year NRM, PFS, and OS.8 While there was no difference in chronic GvHD between the two groups, patients affect- ed by chronic GvHD in the triple-drug group had a trend towards lower NRM after 1 year compared with those in the standard group (4% in triple-drug group vs. 15% in the standard group). Ursodiol use, at a dose of 12 mg/kg/day
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