Hematopoietic cell transplantation (HCT) is the only potentially curative treatment option for many patients with hematologic malignancies. While HCT outcomes have improved drastically over the ...years, patients and clinicians continue to face numerous survivorship challenges, such as relapse, graft-versushost disease, and secondary malignancies. Recent literature suggests that clonal hematopoiesis (CH), the presence of a recurrent somatic mutation in hematopoietic cells, in HCT patients or donors may be associated with outcomes in autologous and allogeneic HCT. Herein, we perform a review of the literature and summarize reported associations between CH and clinical outcomes in HCT. For commonly reported outcomes, we used meta-analysis methods to provide estimates of effect sizes when combining results. A total of 32 articles with relevant and independent contributions were included, covering both autologous (n = 19) and allogeneic (n = 13) HCT. The articles report variable risk for developing outcomes according to CH characteristics, patient disease status, and method of HCT. Using meta-analysis of available results, HCT outcomes with statistically significant effects by CH status include therapy-related myeloid neoplasms (OR 3.65, 95%CI 2.18-6.10) and overall survival (HR 1.38, 95%CI 1.20-1.58) in autologous HCT and relapse (HR 0.80, 95%CI 0.68-0.94) in allogeneic HCT. However, heterogeneity, biases, and limitations in the literature provide challenges for informing the translation of CH to clinical decision-making. We conclude with a call to action and discussion of next steps to build upon the current literature and provide granularity to the true clinical impact of CH in the setting of HCT.
Hematopoietic cell transplantation (HCT) is curative for hematologic disorders, but outcomes are historically inferior when using HLA-mismatched donors. Despite unrelated donor registries listing > ...38 million volunteers, 25%-80% of US patients lack an HLA-matched unrelated donor, with significant disparity across ethnic groups. We hypothesized that HCT with a mismatched unrelated donor (MMUD) using post-transplant cyclophosphamide (PTCy), a novel strategy successful in overcoming genetic disparity using mismatched related donors, would be feasible and increase access to HCT.
We performed a prospective phase II study of MMUD bone marrow HCT with PTCy for patients with hematologic malignancies. The primary end point was 1-year overall survival (OS), hypothesized to be 65% or better. 80 patients enrolled at 11 US transplant centers (December 2016-March 2019). Following myeloablative or reduced-intensity conditioning-based HCT, patients received PTCy on days +3, +4, with sirolimus and mycophenolate mofetil starting on day +5. We compared outcomes to Center for International Blood and Marrow Transplant Research contemporary controls receiving PTCy.
Notably, 48% of patients enrolled were ethnic minorities. 39% of pairs were matched for 4-6 out of 8 HLA alleles. The primary end point was met, with 1-year OS of 76% (90% CI, 67.3 to 83.3) in the entire cohort, and 72% and 79% in the myeloablative and reduced-intensity conditioning strata, respectively. Secondary end points related to engraftment and graft-versus-host-disease were reached. Multivariate analysis comparing the study group with other mismatched HCT controls found no significant differences in OS.
Our prospective study demonstrates the feasibility and effectiveness of HCT with an MMUD in the setting of PTCy. Remarkably, nearly half of the study participants belonged to an ethnic minority population, suggesting this approach may significantly expand access to HCT.
Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic ...graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days -3, -2, -1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P < .001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P = .47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% P = .04 and 59% v 74% P = .034, respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P = .026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P = .01). Conclusion In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.
Depression and fatigue are common among cancer patients and are associated with germline genetic variation. The goal of this pilot study was to examine genetic associations with depression and ...fatigue in the year after allogeneic hematopoietic cell transplant (HCT).
Blood was collected from patients and their donors before HCT. Patients completed self-report measures of depression and fatigue before HCT (T1), 90 days post-HCT (T2), and 1 year post-HCT (T3). Of the 384 genetic variants genotyped on a custom Illumina BeadChip microarray, 267 were retained for analysis based on quality control. Main effects of patient and donor variants as well as their interaction were examined using regression analyses. Significant variants were defined as those with a false discovery rate-adjusted p value of <.05.
The sample consisted of 59 patient-donor pairs. Mean levels of depression and fatigue did not change significantly over time ( p values of > .41). Increases in depression from T1 to T2 were associated with patient-donor interactions at rs1928040 ( p = 3.0 × 10 -4 ) and rs6311 ( p = 2.0 × 10 -4 ) in HTR2A . Increases in fatigue from T1 to T2 were associated with patient rs689021 in SORL1 ( p = 6.0 × 10 -5 ) and a patient-donor interaction at rs1885884 in HTR2A ( p < 1.0 × 10 -4 ).
Data suggest that variants in genes regulating the serotonergic system ( HTR2A ) and lipid metabolism ( SORL1 ) are associated with changes in depression and fatigue in allogeneic HCT patients, implicating patients' own genetic inheritance as well as that of donors. Additional studies are warranted to confirm these findings.
Background
Quantification of skeletal muscle using computed tomography (CT) is accessible using cancer patients' standard oncologic images. Reduced muscle mass may be related to reduced respiratory ...muscle strength; however, the impact of this on lung functional parameters is not characterized in adult allogeneic haematopoietic stem cell transplant (alloHCT) recipients.
Methods
A consecutive retrospective series (n = 296) of patients who had alloHCT at a comprehensive cancer centre between March 2005 and April 2015 were included. Pre‐transplant CT scans were used to quantify skeletal muscle and adipose tissue at the fourth thoracic (T4) and/or third lumbar (L3) level. Tumour and patient characteristics were recorded, including forced expiratory volume in 1 second (FEV1) by spirometry. Regression models were created to characterize predictive relationships.
Results
A total of 296 patients (♂n = 161; ♀n = 135) were included, all of whom had chest CT as part of standard care; a subset of these (n = 215, 72.6%) also had abdominal CT. Diagnoses were non‐Hodgkins lymphoma (n = 165), acute myeloid leukaemia (n = 66), Hodgkin's disease (n = 14), acute lymphocytic leukaemia (n = 14), myelodysplastic syndromes (n = 18), and other (n = 19). In multivariable linear regression adjusted for sex (P < 0.0001), age (P < 0.0001), haematopoietic cell transplantation‐specific co‐morbidity index (P = 0.010), and parameters of pulmonary function testing (defined by spirometry, P < 0.0001), both T4 muscle index β 0.127 (95% confidence interval 0.019; 0.252), P < 0.0001 and T4 muscle radiodensity β 0.132 (95% confidence interval 0.087; 0.505), P = 0.006 were independently associated with FEV1; disease risk index (P = 0.877) and Karnofsky performance status (P = 0.548) were not associated with FEV1. Similar conclusions were obtained when L3 muscle index and radiodensity were considered. Unlike T4, L3 muscle index values can be compared with published cut‐off values for sarcopenia. Overall rates of sarcopenia were uniformly higher in the HCT population than in age‐matched and sex‐matched patients with solid tumours alloHCT ♂64.7% vs. solid tumour ♂56.6% (P < 0.001); alloHCT ♀57.6% vs. solid tumour ♀36.0% (P < 0.001). Significant but moderate correlations (P < 0.001) were found for muscle area and radiodensity between L3 and T4, for both men and women; adipose tissue quantity also correlated significantly (P < 0.001) between L3 and T4 for both men and women.
Conclusions
Lumbar or thoracic CT images are useful for body composition assessment in this population and reveal high rates of sarcopenia, similar to those reported in very elderly patients. Reduced muscle mass and radiodensity associate with impaired FEV1 even after adjustment for clinical covariables including co‐morbidities, performance status, disease risk, and mild intrinsic pulmonary disease (chronic obstructive pulmonary disease) defined by spirometry.
Positive results from recent clinical trials have significantly expanded current therapeutic options for patients with chronic graft-versus-host disease (GVHD). However, new insights into the ...associations between clinical characteristics of chronic GVHD, pathophysiologic mechanisms of disease, and the clinical and biological effects of novel therapeutic agents are required to allow for a more individualized approach to treatment. The current report is focused on setting research priorities and direction in the treatment of chronic GVHD. Detailed correlative scientific studies should be conducted in the context of clinical trials to evaluate associations between clinical outcomes and the biological effect of systemic therapeutics. For patients who require systemic therapy but not urgent initiation of glucocorticoids, clinical trials for initial systemic treatment of chronic GVHD should investigate novel agents as monotherapy without concurrently starting glucocorticoids, to avoid confounding biological, pathological, and clinical assessments. Clinical trials for treatment-refractory disease should specifically target patients with incomplete or suboptimal responses to most recent therapy who are early in their disease course. Close collaboration between academic medical centers, medical societies, and industry is needed to support an individualized, biology-based strategic approach to chronic GVHD therapy.
Chronic graft-versus-host disease (cGVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. To better understand patients at highest risk for ...nonrelapse mortality (NRM), we analyzed patient-, transplant-, and cGVHD-related variables, risk factors, and causes of nonrelapse deaths in an updated cohort of 937 patients enrolled on 2 prospective, longitudinal observational studies through the Chronic GVHD Consortium. The median follow-up of survivors was 4 years (range, 0.1 months to 12.5 years). Relapse accounted for 25% of the 333 deaths. The cumulative incidence of NRM was 22% at 5 years, and it increased over time at a projected 40% (95% confidence interval, 30%-50%) at 12 years. Centers reported that cGVHD (37.8%) was the most common cause of NRM and was associated with organ failure, infection, or additional causes not otherwise specified. The next most frequent causes without mention of cGVHD were infection (17%) and respiratory failure (10%). In multivariable analysis, an increased risk for NRM was significantly associated with the use of reduced intensity conditioning, higher total bilirubin, National Institutes of Health (NIH) skin score of 2 to 3, NIH lung score of 1 to 3, worse modified Human Activity Profile adjusted activity score, and decreased distance on walk test. To summarize, cGVHD NRM does not plateau but increases over time and is most commonly attributed to GVHD or infection, presumably associated with immunocompromised status. Severe skin and lung cGVHD remain challenging manifestations associated with increased NRM, for which novel therapeutic options that do not predispose patients to infections are needed.
•NRM increases without apparent plateau in patients with cGVHD.•The most common reported causes of death were cGVHD and infection.
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-PROM total score, PROM total score change, and NIH 0-3 skin change are associated with clinician-reported response in cutaneous sclerosis-HAP AAS, SF36 vitality change, LSS skin, and LSS skin change ...are associated with patient-reported response in cutaneous sclerosis
Cutaneous sclerosis, a highly morbid subtype of chronic graft vs. host disease (cGVHD), demonstrates limited treatment response under current NIH Response Measures. We explored novel sclerosis-specific response measures using Chronic GVHD Consortium data. A training cohort included patients with cutaneous sclerosis from a randomized trial of imatinib vs. rituximab, and a Consortium observational study. The validation cohort was a different Consortium observational study. Clinician-reported measures (baseline, and baseline to 6-month change) were examined for association with 6-month clinician-reported response. Patient-reported measures (baseline and baseline to 6-month change) were studied for association with 6-month patient-reported response. A total of 347 subjects were included (training 183, validation 164). While multiple skin and joint measures were associated with clinician-reported response on univariate analysis, PROM total score, PROM total score change, and NIH 0-3 skin change were retained in the final multivariate model (AUC 0.83 training, 0.75 validation). Similarly, many patient-reported measures were associated, but final multivariate analysis retained the HAP AAS, SF36 vitality change, LSS skin, and LSS skin change in the model (AUC 0.86 training, 0.75 validation). We identified which sclerosis measures have greatest association with 6-month clinician- and patient-reported treatment response, a previously unstudied area. However, given the observed performance in the validation cohorts, we conclude that further work is needed. Novel response measures may be needed to optimally assess treatment response in cutaneous sclerosis.
Quantification of skeletal muscle using computed tomography (CT) is accessible using cancer patients' standard oncologic images. Reduced muscle mass may be related to reduced respiratory muscle ...strength; however, the impact of this on lung functional parameters is not characterized in adult allogeneic haematopoietic stem cell transplant (alloHCT) recipients.
A consecutive retrospective series (n = 296) of patients who had alloHCT at a comprehensive cancer centre between March 2005 and April 2015 were included. Pre-transplant CT scans were used to quantify skeletal muscle and adipose tissue at the fourth thoracic (T4) and/or third lumbar (L3) level. Tumour and patient characteristics were recorded, including forced expiratory volume in 1 second (FEV
) by spirometry. Regression models were created to characterize predictive relationships.
A total of 296 patients (♂n = 161; ♀n = 135) were included, all of whom had chest CT as part of standard care; a subset of these (n = 215, 72.6%) also had abdominal CT. Diagnoses were non-Hodgkins lymphoma (n = 165), acute myeloid leukaemia (n = 66), Hodgkin's disease (n = 14), acute lymphocytic leukaemia (n = 14), myelodysplastic syndromes (n = 18), and other (n = 19). In multivariable linear regression adjusted for sex (P < 0.0001), age (P < 0.0001), haematopoietic cell transplantation-specific co-morbidity index (P = 0.010), and parameters of pulmonary function testing (defined by spirometry, P < 0.0001), both T4 muscle index β 0.127 (95% confidence interval 0.019; 0.252), P < 0.0001 and T4 muscle radiodensity β 0.132 (95% confidence interval 0.087; 0.505), P = 0.006 were independently associated with FEV
; disease risk index (P = 0.877) and Karnofsky performance status (P = 0.548) were not associated with FEV
. Similar conclusions were obtained when L3 muscle index and radiodensity were considered. Unlike T4, L3 muscle index values can be compared with published cut-off values for sarcopenia. Overall rates of sarcopenia were uniformly higher in the HCT population than in age-matched and sex-matched patients with solid tumours alloHCT ♂64.7% vs. solid tumour ♂56.6% (P < 0.001); alloHCT ♀57.6% vs. solid tumour ♀36.0% (P < 0.001). Significant but moderate correlations (P < 0.001) were found for muscle area and radiodensity between L3 and T4, for both men and women; adipose tissue quantity also correlated significantly (P < 0.001) between L3 and T4 for both men and women.
Lumbar or thoracic CT images are useful for body composition assessment in this population and reveal high rates of sarcopenia, similar to those reported in very elderly patients. Reduced muscle mass and radiodensity associate with impaired FEV
even after adjustment for clinical covariables including co-morbidities, performance status, disease risk, and mild intrinsic pulmonary disease (chronic obstructive pulmonary disease) defined by spirometry.
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