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J.P. Cooper et al.
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TBI: total body irradiation; Gy: Gray; GvHD: graft-versus-host disease; CI: calcineurin inhibitor; MMF: mycophenolate mofetil; FH: Fred Hutchinson Cancer Research Center; ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; CLL: chronic lymphocytic leukemia; CML: chronic myelogenous leukemia; HL: Hodgkin lymphoma; MDS: myelodys- plastic syndromes; MPN: myeloproliferative neoplasms; MM: multiple myeloma; NHL: non-Hodgkin lymphoma; WM: Waldenström macroglobulinemia; CMV: cytomegalovirus; R: recipient; D: donor; HCT-CI: hematopoietic cell transplantation comorbidity index; GCSF: granulocyte colony-stimulating factor; PBSC: peripheral blood stem cells. aFludarabine was given at a dose of 30 mg/m2/day IV on days 4, 3, and 2 before HCT. Clofarabine was given at a dose of 30-50 mg/m2/day on days 6, 5, 4, 3, and 2 before HCT.TBI was given on the day before donor hematopoietic cell infusion. bAll related (n=815) and most unrelated recipients (n=727) received MMF for at least 28 days after related HCT and 56 days after unrelated HCT, with either cyclosporine or tacrolimus, for at least 80 days, with the majority of patients receiving a calcineurin inhibitor for 150–180 days after HCT. The remaining unrelated recipients (n=178 total – zero during 1997–2003, 65 during 2004–2009, and 113 during 2010–2017) received sirolimus from day -3 to either day 80 or 180, in addition to MMF (days zero to 40 or 96) and cyclosporine (days -3 to 150–180). cOn-protocol patients were those transplanted on active clinical trials. Off-protocol patients were those transplanted outside of an active clinical study. All patients signed consent giving permission for their clinical data to be used for research studies such as this one. dGCSF- mobilized PBSC grafts contained a median of 8.0×106 CD34+ cells/kg (range,0.2-42.6×106 CD34+ cells/kg) and 3.1×108 CD3+ cells/kg (range,0.1-296.0×108 CD3+ cells/kg).eKahl dis- ease risk groups assigned as described.20 fHematopoietic cell transplantation comorbidity index (HCT-CI) assigned as described.17 gDonors and recipients were matched at HLA- A, -B, -C, -DRB1, and -DQB1 by high-resolution typing except for the specified number of unrelated donor-recipient pairs who were mismatched at the level of one HLA class I allele.hIncludes planned autologous,failed autologous,and failed allogeneic transplantation.The number of patients who had a prior planned autologous HCT decreased from 107 (19%) during 1997–2003 to one during 2010–2017; 23 patients (4%) had an unsuccessful prior autologous HCT during 1997–2003, increasing to 120 patients (21%) during 2010–2017; 3 patients (<1%) had an unsuccessful prior allogeneic HCT during 1997–2003, increasing to 22 patients (4%) during 2010–2017. iP-values reflect any pattern of vari- ation over the three time periods, including trends over time.
1997–2003, 594 from 2004–2009, and 564 from 2010– 2017. An increasing number and proportion of patients underwent HCT at FHCRC over time (P<0.0001) on pro- tocols considered standard-of-care. The proportion of patients age ≥60 years at the time of HCT increased, as did the proportion of patients with an HCT-CI score ≥3. Unrelated donors were utilized more frequently over time. The distribution of diagnoses changed over time (P<0.0001), most notably with an increase in the propor- tion of patients with AML (16% during 1997–2003 and 30% during 2010–2017) and decreases in CML and multi- ple myeloma.
The distribution of disease relapse risk groups 20 changed over time (P<0.0001), with a decreasing propor- tion of patients with high-risk disease and an increasing proportion with low-risk disease.
A minority of patients had a prior HCT, but the types of prior HCT changed over time. The number of patients who had a prior planned autologous HCT decreased from 107 (19%) during 1997–2003 to one during 2010–2017, while the number of patients who had unsuccessful prior autologous or allogeneic HCT increased (Table 1). Planned autologous HCT were typically performed in conjunction with a tandem allogeneic HCT for patients with multiple myeloma.
Major endpoints by era of transplant
Associations of major endpoints with the time period of HCT are summarized in Table 2 and Figures 1 and 2. As described in the Methods section, results were adjusted for risk factors that varied over the three time periods and were potentially related to one or more endpoints of inter- est. OS, PFS, and NRM all had a significant association with the era of HCT. When compared to 1997–2003, sig- nificant improvements were noted during 2004 –2009 and 2010–2017 for OS (hazard ratio [HR] 0.72, P=0.0001 and HR 0.60, P<0.0001), PFS (HR 0.78, P=0.002 and HR 0.63, P<0.0001), and NRM (HR 0.58, P<0.0001 and HR 0.52, P<0.0001). The risk of relapse or progression was lower during 2010–2017 when compared to 1997–2003 (HR 0.71, P=0.006). The incidence of relapse-related mortality trended toward improvement in later time periods, but the differences from 1997– 003 were not statistically sig- nificant.
Rates of grades 2–4 acute GvHD, grades 3–4 acute GvHD, and chronic GvHD were all significantly associat- ed with time period of HCT and, when compared to 1997– 2003, all improved significantly during 2004–2009 and 2010–2017. Given we increasingly used ‘triple
immunosuppression’ consisting of MMF, a calcineurin inhibitor, and sirolimus for patients undergoing HCT from unrelated donors,6,8 we evaluated its impact on acute GvHD separately. Adding sirolimus reduced the rates of grades 2–4 and 3–4 acute GvHD when compared to patients who received MMF and a calcineurin inhibitor without sirolimus (HR 0.52, 95% CI: 0.40–0.67, P<0.0001 and HR 0.54, 95% CI: 0.29–1.01, P=0.05, respectively).
Association of relapse or progression with era of transplant in patients with acute myeloid leukemia in remission
Since the overall rate of relapse or progression was sig- nificantly decreased in the most recent time period, we evaluated whether this was also true for the 351 patients with AML in first or second complete remission (CR1/CR2): 64 during 1997–2003, 147 during 2004–2009, and 140 during 2010–2017. Among these patients, meas- urable (minimal) residual disease (MRD) at the time of HCT as determined by flow cytometry, cytogenetics, or molecular analysis was detected in 16 patients (11%) dur- ing 2004– 2009 and 32 patients (23%) during 2010–2017. Data were unavailable prior to 2004. We found no statis- tically significant change in the rate of relapse for patients with AML in CR1/CR2 over time. When compared to 1997–2003, the adjusted HR for relapse during 2004–2009 was 0.84 (95% CI: 0.4–1.6, P=0.61) and during 2010–2017 was 0.89 (95% CI: 0.4–1.8, P=0.75).
Associations of organ complications and infections with era of transplant
Associations of liver and kidney injuries, gram-negative bacteremia, invasive fungal infections, and CMV infection with era of HCT are shown in Table 3. Compared to 1997–2003, the incidences of patients having liver or kid- ney complications, gram-negative bacteremia, or an inva- sive fungal infection through day 100 were significantly lower in the two most recent time periods of HCT.
Serologic CMV infection was evaluated in recipients who were seropositive at the time of HCT as these patients were at the highest risk for development of CMV disease and CMV-associated mortality.28 CMV diagnostic testing evolved during the three time periods, and we included measurement via both the pp65 antigen detec- tion assay and PCR-based detection of CMV DNA in plas- ma in our analysis. While the incidence of CMV reactiva- tion did not significantly change over time, the incidence of CMV disease was significantly decreased in the most recent era (P=0.001).
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