Page 98 - 2021_06-Haematologica-web

J.P. Cooper et al.
NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.
Introduction
In 1997 we introduced a minimally intensive condition- ing regimen for allogeneic hematopoietic cell transplanta- tion (HCT) that enabled treating elderly and medically infirm younger patients with advanced hematologic malignancies in the outpatient setting. We previously reported outcomes for patients who underwent HCT from 1997–2009 using this regimen, which included low- dose total body irradiation (TBI) with or without fludara- bine.1 Five-year overall survival ranged from 25% to 60% (depending on disease type, comorbidities, and graft-ver- sus-host disease [GvHD]), non-relapse mortality (NRM) was 24%, and relapse-related mortality was 35%. The most significant contributor to NRM was GvHD.
Between 1997 and 2017 a number of changes in clinical practice were introduced that were aimed at improving HCT outcomes including reductions in the use of systemic glucocorticoids as treatment for acute GvHD,2,3 use of ursodiol to reduce hepatic complications,4,5 addition of sirolimus for control of GvHD,6-8 use of fluoroquinolones for antibacterial prophylaxis during periods of neutrope- nia,9-11 use of more mold-active azoles for antifungal pro- phylaxis,12,13 and initiation of pre-emptive antiviral therapy based on more sensitive polymerase chain reaction (PCR)- based cytomegalovirus (CMV) diagnostic testing.14-16
During the same time period, patient and donor charac- teristics as well as indications for HCT also changed. The proportion of patients older than 60 years increased from 27% to 56%, proportion of patients with hematopoietic cell transplantation-comorbidity index (HCT-CI)17 scores ≥3 increased from 25% to 45%, use of unrelated donors increased from 35% to 65%, and increasing numbers of patients underwent HCT for acute myeloid leukemia (AML) while decreasing numbers of patients underwent HCT for multiple myeloma and chronic myelogenous leukemia (CML). The current study analyzed whether benefits associated with the changes in clinical care for patients undergoing HCT outweighed the adverse out- comes expected from older patient age, increased comor- bidities, and greater use of unrelated donors. To that end, we compared outcomes in three cohorts of patients by year of HCT: 1997–2003, 2004– 2009, and 2010–2017.
Methods
Patients
Between December 16, 1997 and June 30, 2017, 1,720 consecu- tive patients with hematologic malignancies underwent HCT at the Fred Hutchinson Cancer Research Center (FHCRC) or collab- orating centers. We included patients who were entered onto prospective clinical trials registered with clinicaltrials.gov at both FHCRC and collaborating centers (Online Supplementary Table S1), and patients transplanted outside of prospective trials at FHCRC. This study was approved by the Institutional Review Board (IRB) at FHCRC and all patients signed IRB-approved con- sents.
Graft source, conditioning, and post-engraftment immunosuppression
All patients received unmodified grafts consisting of granulo- cyte colony-stimulating factor (GCSF)-mobilized peripheral blood stem cells (PBSC). Donors and recipients were matched at HLA-A, -B, -C, -DRB1, and -DQB1 by high-resolution typing except for 104 unrelated donor-recipient pairs who were mismatched at the level of one HLA class I allele. Conditioning regimens and immunosuppression to aid engraftment and control GvHD are summarized in the Online Supplementary Table S1.
Clinical endpoints
Patients had bone marrow aspirations to assess disease status on days 28, 84, and 365 after HCT, and otherwise as clinically indi- cated. Acute and chronic GvHD were diagnosed and graded as previously described.18,19 Relapse was defined as recurrence of malignancy based on imaging, marrow morphology, flow cytom- etry, cytogenetics, and/or disease-specific molecular markers. Progression was defined as ≥50% increase in disease burden.20 Relapse-related mortality included deaths after relapse or progres- sion of disease present before HCT, regardless of other events. NRM included deaths in the absence of relapse or progression.
Clinical assessment of organ complications and infections through day 100
Liver injury was assessed according to peak bilirubin concentra- tion.19 Acute kidney injury was defined as a serum creatinine con- centration that was at least 2-fold higher than the baseline value.21 CMV infection was defined as the presence of pp65 antigen or DNA in plasma,22 and CMV disease was defined as dysfunction of an organ infected by CMV.23 One or more positive blood cultures for gram-negative bacteria were defined as gram-negative bac- teremia; gram-negative organisms tend to cause the most serious infections in patients who are neutropenic after HCT.24 Invasive fungal infections were defined according to consensus criteria and included cases deemed proven or probable.25
Statistical analysis
Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Rates of acute and chronic GvHD, relapse or progression, and NRM were estimated according to standard methods.26 Death was treated as a compet- ing risk factor for all other time-to-event endpoints. Relapse was treated as a competing risk for NRM. Relapse-related mortality refers to survival after relapse among patients that relapsed. Multivariate Cox regression analysis of cause-specific hazards, stratified by center, was used for adjusted comparisons between groups defined by year of HCT. Adjusted estimates of survival and cumulative incidence were based on methods previously described.27 Briefly, the adjusted curves represent the hypothetical outcomes for the three transplant eras if each era had the patient characteristics of the first era, based on results from the adjusted Cox regression models. Multivariate logistic regression was used for adjusted comparisons of rates of elevated bilirubin and creati- nine. The adjusted models included the following variables that varied over era of HCT and were potentially related to one or more endpoints: treatment type (on-protocol, off-protocol); age (≤49, 50–59, or ≥60 years); disease relapse risk (low, standard,
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