Bone Marrow Transplant
BACKGROUND: Low-intensity regimens have been increasingly used to treat older patients with acute myeloid leukemia (AML). Recent studies, however, suggest older patients can tolerate and potentially benefit from intensive chemotherapeutic regimens. The ability to compare the utility of varying regimen intensities in AML is hindered by the lack of a standardized definition of "regimen intensity." METHODS: We conducted a survey asking AML physicians which of 38 regimens they would consider intensive vs less-intensive. Electronic medical records of 592 patients receiving many of these regimens were used to design a model characterizing regimens as intensive vs less-intensive as identified by 75% physician consensus. Variables included frequency and length of hospitalizations, intensive care unit admissions, severe gastrointestinal toxicities, time to nadir, and recovery of neutrophil/platelet count. RESULTS: Physicians agreed at a rate of 75%-100% on the assignment of degree of intensity to the majority (n=28) of these regimens, while the level of agreement was <75% for the remaining 10 regimens (26%). Logistic regression analyses identified number and length of hospitalizations to be significantly associated with intensive regimens and count recovery with less-intensive regimens. We created the "regimen-intensity per count-recovery and hospitalization" (RICH) index with an AUC of 0.87. Independent model validation yielded an AUC of 0.75. CONCLUSIONS: We were able to generate a novel model that defines regimen intensity for many therapies used to treat AML. Results facilitate a future randomized study comparing intensive vs less-intensive regimens.
Few patients with cancer, including those with acute myeloid leukemia and high-grade myeloid neoplasms, participate in clinical trials. Broadening standard eligibility criteria may increase clinical trial participation. In this retrospective single-center analysis, we identified 442 consecutive newly diagnosed patients from 2014 to 2016. Patients were considered eligible if they had performance status 0-2, normal renal and hepatic function, no recent solid tumor, left ventricular ejection fraction (EF) ≥ 50%, and no history of congestive heart failure (CHF) or myocardial infarction (MI); ineligible patients failed to meet one or more of these criteria. We included 372 patients who received chemotherapy. Ineligible patients represented 40% of the population and had a 1-79-fold greater risk of death (95% CI 1.37, 2.33) than eligible patients. Very few patients had cardiac co-morbidities, including 2% with low EF, 4% with prior CHF, and 5% with prior MI. In multivariable analysis, ineligibility was associated with decreased survival [HR 1-44 (95% CI 1-07, 1-93)]. Allogeneic transplantation, performed in 150 patients (40%), was associated with improved survival [HR 0-66, 95% CI (0-48, 0-91)]. Therefore, standard eligibility characteristics identify a patient population with improved survival. Further treatment options are needed for patients considered ineligible for clinical trials.
We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.
J Palliat Med
Background: Multiple chronic conditions (MCCs) are associated with increased intensity of end-of-life (EOL) care, but their effect is not well explored in patients with cancer. Objective: We examined EOL health care intensity and advance care planning (ACP) documentation to better understand the association between MCCs and these outcomes. Design: Retrospective cohort study. Setting/Subjects: Patients aged 18+ years at UW Medicine who died during 2010-2017 with poor prognosis cancer, with or without chronic liver disease, chronic pulmonary disease, coronary artery disease, dementia, diabetes with end-stage organ damage, end-stage renal disease, heart failure, or peripheral vascular disease. Measurements: ACP documentation 30+ days before death, in-hospital death, and inpatient or intensive care unit (ICU) admission in the last 30 days. We performed logistic regression for outcomes. Results: Of 15,092 patients with cancer, 10,596 (70%) had 1+ MCCs (range 1-8). Patients with cancer and heart failure had highest odds of hospitalization (odds ratio [OR] 1.67, 95% confidence interval [CI] 1.46-1.91), ICU admission (OR 2.06, 95% CI 1.76-2.41), or in-hospital death (OR 1.62, 95% CI 1.43-1.84) versus patients with cancer and other conditions. Patients with ACP 30+ days before death had lower odds of in-hospital death (OR 0.65, 95% CI 0.60-0.71), hospitalization (OR 0.67, 95% CI 0.61-0.74), or ICU admission (OR 0.71, 95% CI 0.64-0.80). Conclusions: Patients with ACP 30+ days before death had lower odds of high-intensity EOL care. Further research needs to explore how to best use ACP to ensure patients receive care aligned with patient and family goals for care.
Clin Cancer Res
Purpose: To develop a prognostic model and cytogenetic risk classification for previously treated patients with chronic lymphocytic leukemia (CLL) undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT).Experimental Design: We performed a retrospective analysis of outcomes of 606 patients with CLL who underwent RIC allogeneic HCT between 2008 and 2014 reported to the Center for International Blood and Marrow Transplant Research.Results: On the basis of multivariable models, disease status, comorbidity index, lymphocyte count, and white blood cell count at HCT were selected for the development of prognostic model. Using the prognostic score, we stratified patients into low-, intermediate-, high-, and very-high-risk [4-year progression-free survival (PFS) 58%, 42%, 33%, and 25%, respectively, P < 0.0001; 4-year overall survival (OS) 70%, 57%, 54%, and 38%, respectively, P < 0.0001]. We also evaluated karyotypic abnormalities together with del(17p) and found that del(17p) or >/=5 abnormalities showed inferior PFS. Using a multivariable model, we classified cytogenetic risk into low, intermediate, and high (P < 0.0001). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (61% at 4 years) and OS (75% at 4 years).Conclusions: In this large cohort of patients with previously treated CLL who underwent RIC HCT, we developed a robust prognostic scoring system of HCT outcomes and a novel cytogenetic-based risk stratification system. These prognostic models can be used for counseling patients, comparing data across studies, and providing a benchmark for future interventions. For future study, we will further validate these models for patients receiving targeted therapies prior to HCT.
Int J Cardiol
BACKGROUND: A Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) was previously developed showing that multiple comorbidities including moderate or greater valvular heart disease to be predictors of non-relapse mortality after allogeneic HCT. However, detailed description of the impact of valve disease on outcomes is lacking. METHODS: Among a large cohort of patients given allogeneic HCT between 2000 and 2017, we identified 21 patients with moderate or severe valvular disease. We also identified a cohort of 42 controls matched on age and HCT-CI score. The primary outcome was all-cause mortality, with censoring at two years of follow-up. Secondary outcomes included mortality without relapse, duration of index admission, number of readmissions, increase in creatinine and peak troponin. RESULTS: Non-myeloablative regimens were more common in the valve disease cohort compared to controls (86% vs 54% p=0.012). Valvular disease was associated with increased all-cause mortality with adjusted hazard ratio of 2.17 (CI 1.08-4.34, p=0.029) and for non-relapse mortality with adjusted hazard ratio of 2.53 (CI 1.16-5.52, p=0.020). In the valve disease cohort, creatinine increased by 1.6 vs 0.9mg/dL (p=0.003) and peak troponin by 1.6 vs 0.3ng/mL (p=0.05) compared to controls. There was no difference in readmissions or length of stay when accounting for outpatient treatment. CONCLUSIONS: Despite having similar pre-procedure risk factors and undergoing less aggressive chemotherapy regimens, patients with moderate valvular disease or greater, most of whom did not meet current guideline recommendations for repair, had worse non-relapse related outcomes with higher mortality, renal and myocardial injury.
Despite overall improvements, mortality after allogeneic hematopoietic cell transplantation (HCT) for non-malignant diseases remains a significant problem. We evaluated whether pre-HCT conditions defined by the HCT Comorbidity Index (HCT-CI), predicts probability of post-transplant survival in these patients. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 4,083 patients with non-malignant diseases transplanted between 2007-2014. Primary outcome was overall survival (OS), estimated using the Kaplan-Meier method. Hazard ratios (HR) were estimated by multivariable Cox regression models. Increasing HCT-CI scores translated to decreased 2-year OS of 82.7%, 80.3%, 74%, 55.8% for patients with HCT-CI scores of 0, 1-2, 3-4, >/=5, respectively (log-rank p<0.001), regardless of conditioning intensity. HCT-CI scores of 1-2 did not differ relative to scores of 0, [HR 1.12 (0.93-1.34, p=0.218)], but HCT-CI of 3-4 and >/=5 posed significantly greater risks of mortality [HR 1.33 (95% CI 1.09-1.63), p=0.004; HR 2.31 (95% CI 1.79-2.96), p<0.0001, respectively). The impact of HCT-CI differed by disease indication. Patients with acquired aplastic anemia, primary immune deficiencies, and congenital bone marrow failure syndromes with scores of >/=3 had increased risk of death after HCT (p<0.001). However, higher HCT-CI scores among hemoglobinopathy patients did not increase mortality risk (p=0.11). In conclusion, this is the largest study to date reporting on patients with non-malignant diseases, demonstrating HCT-CI scores >/= 3 had inferior survival after HCT, except for patients with hemoglobinopathies. Our findings suggest that using the HCT-CI score,in addition to disease-specific factors, could be useful when developing treatment plans for non-malignant diseases.
Biol Blood Marrow Transplant
The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) was developed and validated to weigh the burden of pretransplant comorbidities and estimate their impact on post-transplant risks of non-relapse mortality (NRM). Recently, the HCT-CI was augmented by the addition of both age and values of three markers namely, ferritin, albumin, and platelet count. The HCT-CI research so far has been almost exclusively limited to recipients of allogeneic HCT from human leucocyte antigen (HLA)-matched grafts. To this end, we sought to investigate the discriminative capacity of an augmented comorbidity/age index among 724 recipients of allogeneic HCT from HLA-mismatched (MM, n=345), haploidentical (n=117), and umbilical cord blood (UCB, n=262) grafts between 2000 and 2013. In the overall cohort, the augmented comorbidity/age index had a higher c-statistic estimate for prediction of NRM compared to the original HCT-CI (0.63 versus 0.59). Findings were similar for recipients of HLA-mismatched (0.62 versus 0.59), HLA-haploidentical (0.60 versus 0.54), or UCB grafts (0.65 versus 0.61). Patients with scores of <4 had higher survival rates compared to those with scores of >/=4 and received HLA-mismatched (55% versus 39%, p<0.0008), HLA-haploidentical (58% versus 38%, p=0.01), or UCB grafts (67% versus 48%, p=0.004), respectively. Our results demonstrate the utility of the augmented comorbidity/age index as a valid prognostic tool among recipients of allogeneic HCT from alternative graft sources.