After more than 60 years of research in allogeneic hematopoietic cell transplantation (HCT), this therapy has advanced from one that was declared dead in the 1960s to a standard treatment of ...otherwise fatal malignant and non-malignant blood diseases. To date, close to 1.5 million hematopoietic cell transplants have been performed in more than 1,500 transplantation centers worldwide. This review will highlight the enormous efforts by numerous investigators throughout the world who have brought the experimental field of HCT to clinical reality, examine ongoing challenges, and provide insights for the future.
Age has long been used as a major factor for assessing suitability for allogeneic hematopoietic cell transplantation (HCT). The HCT-comorbidity index (HCT-CI) was developed as a measure of health ...status to predict mortality risk after HCT. Whether age, comorbidities, or both should guide decision making for HCT is unknown.
Data from 3,033 consecutive recipients of HLA-matched grafts from five institutions contributed to this analysis. Patients were randomly divided into a training set to develop weights for age intervals and a validation set to assess the performance of prognostic models.
In the training set, patients age 20 to 39 years, 40 to 49 years, 50 to 59 years, and ≥ 60 years had hazard ratios for nonrelapse mortality (NRM) of 1.21 (P = .29), 1.48 (P = .04), 1.75 (P = .004), and 1.84 (P = .005), respectively, compared with those age younger than 20 years. Consequently, age ≥ 40 years was assigned a weight of 1 to be added to the HCT-CI to constitute a composite comorbidity/age index. In the validation set, the composite comorbidity/age score had statistically significantly higher c-statistic estimates for prediction of NRM (0.664 v 0.556; P < .001) and survival (0.682 v 0.560; P < .001) compared with age, respectively. Patients with comorbidity/age scores of 0 to 2 had comparable mortality risks regardless of conditioning regimens. Patients with scores of 3 to 4 and ≥ 5 had statistically significant higher mortality risks after high-dose versus nonmyeloablative regimens.
Age is a poor prognostic factor. The proposed composite measure allows integration of both comorbidities and age into clinical decision making and comparative-effectiveness research of HCT.
Allogeneic hematopoietic stem cell transplantation is an established treatment modality for malignant and nonmalignant hematologic diseases. Acute and chronic graft-versus-host diseases (GVHDs) are a ...major cause of morbidity and mortality after allogeneic stem cell transplantation. T cells have been identified as key players in the graft-versus-host reaction and, therefore, most established drugs used against GVHD target T cells. Despite our knowledge on the pathogenesis of the GVH reaction, success of established therapies for prevention and treatment of GHVD is unsatisfactory. Recently, animal and human studies demonstrated that B cells are involved in the immunopathophysiology of acute and chronic GVHD. Early phase clinical trials of B-cell depletion with rituximab have shown beneficial effects on both acute and chronic GVHD. This review summarizes the current experimental and clinical evidence for the involvement of B cells in the pathogenesis of acute and chronic GVHD and discusses the clinical implications for the management of patients undergoing allogeneic stem cell transplantation.
Allogeneic hematopoietic cell transplantation is indicated for refractory hematologic cancer and some nonmalignant disorders. Survival is limited by recurrent cancer and organ toxicity.
To determine ...whether survival has improved over the past decade and note impediments to better outcomes.
The authors compared cohorts that had transplants during 2003 to 2007 versus 2013 to 2017. Survival outcome measures were analyzed, along with transplant-related complications.
A center performing allogeneic transplant procedures.
All recipients of a first allogeneic transplant during 2003 to 2007 and 2013 to 2017.
Patients received a conditioning regimen, infusion of donor hematopoietic cells, then immunosuppressive drugs and antimicrobial approaches to infection control.
Day-200 nonrelapse mortality (NRM), recurrence or progression of cancer, relapse-related mortality, and overall mortality, adjusted for comorbidity scores, source of donor cells, donor type, patient age, disease severity, conditioning regimen, patient and donor sex, and cytomegalovirus serostatus.
During the 2003-to-2007 and 2013-to-2017 periods, 1148 and 1131 patients, respectively, received their first transplant. Over the decade, decreases were seen in the adjusted hazards of day-200 NRM (hazard ratio HR, 0.66 95% CI, 0.48 to 0.89), relapse of cancer (HR, 0.76 CI, 0.61 to 0.94), relapse-related mortality (HR, 0.69 CI, 0.54 to 0.87), and overall mortality (HR, 0.66 CI, 0.56 to 0.78). The degree of reduction in overall mortality was similar for patients who received myeloablative versus reduced-intensity conditioning, as well as for patients whose allograft came from a matched sibling versus an unrelated donor. Reductions were also seen in the frequency of jaundice, renal insufficiency, mechanical ventilation, high-level cytomegalovirus viremia, gram-negative bacteremia, invasive mold infection, acute and chronic graft-versus-host disease, and prednisone exposure.
Cohort studies cannot determine causality, and current disease severity criteria were not available for patients in the 2003-to-2007 cohort.
Improvement in survival and reduction in complications were substantial after allogeneic transplant. Relapse of cancer remains the largest obstacle to better survival outcomes.
National Institutes of Health.
Risk factors for grades 2-4 acute graft-versus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients ...of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD.
Most hematological malignancies occur in older patients. Until recently these patients and those with comorbidities were not candidates for treatment with allogeneic hematopoietic transplantation ...because they were unable to tolerate the heretofore used high-dose conditioning regimens. The finding that many of the cures achieved with allogeneic hematopoietic transplantation were due to graft-versus-tumor effects led to the development of less toxic and well-tolerated reduced intensity and nonmyeloablative regimens. These regimens enabled allogeneic engraftment, thereby setting the stage for graft-versus-tumor effects. This review summarizes the encouraging early results seen with the new regimens and discusses the two hurdles that need to be overcome for achieving even greater success, disease relapse and graft-versus-host disease.
We analyzed subsequent cancers in 329 patients with aplastic anemia given HLA-matched related marrow grafts. Median follow-up: 26 (range 1-47) years. Conditioning: cyclophosphamide ± antithymocyte ...globulin; graft-vs.-host disease (GVHD) prevention: methotrexate ± cyclosporine. The long follow-up and homogeneous treatment allowed definitive analyses of incidence, nature, time of onset, and potential causes of cancers. Fifty-three cancers occurred in 46 patients, 42 had solid tumors and 4 blood cancers. Of the 42, 22 had non-melanoma skin and 7 oropharyngeal cancers. The remainder had a spectrum of other cancers including two liver cancers from pre-transplant hepatitis C. The 26-year cumulative incidence (CI) of cancer was 11% and mortality 5%. Excluding non-melanoma skin cancers, the 26-year CI of cancer was 7%. Cancers were 2.03-fold more than expected from SEER data; that number was 1.89-fold after excluding liver cancers. Nearly all cancers developed between 14 and 34 years. Skin and oropharyngeal cancers showed significant association with chronic GVHD, whereby GVHD had resolved in most patients within 7 years of transplantation. Thus, tumors evolved after a lag time of 7-27 years. Other cancers showed no clear associations with chronic GVHD or drugs used for transplantation. Results reemphasize the importance of preventing chronic GVHD.
Allogeneic stem cell transplantation (alloSCT) is an effective immunotherapy in patients with hematological malignancies. Endothelial dysfunction was linked to major complications after alloSCT. We ...asked the question if the "Endothelial Activation and Stress Index" (EASIX; (creatinine × LDH) ÷ thrombocytes) can predict mortality after alloSCT. We performed a retrospective cohort analysis in five alloSCT centers in the USA and Germany. EASIX was assessed prior to conditioning (EASIX-pre) and correlated with mortality in 755 patients of a training cohort in multivariable models. The predictive model established in the training cohort was validated in 1267 adult allo-recipients. Increasing EASIX-pre predicted lower overall survival (OS) after alloSCT, and successful model validation was achieved for the validation cohort. We found that EASIX-pre predicts OS irrespective of established scores. Moreover, EASIX-pre was also a significant prognostic factor for transplant-associated microangiopathy. Finally, EASIX-pre correlated with biomarkers of endothelial homeostasis such as CXCL8, interleukin-18, and insulin-like-growth-factor-1 serum levels. This study establishes EASIX-pre based on a standard laboratory biomarker panel as a predictor of individual risk of mortality after alloSCT independently from established clinical criteria.
PURPOSE Hematopoietic cell transplantation can cure hematologic malignancies and other diseases, but this treatment can also cause late complications. Previous studies have evaluated the cumulative ...effects of late complications on survival, but longer-term effects on life expectancy after hematopoietic cell transplantation have not been assessed. PATIENTS AND METHODS We used standard methods to evaluate mortality, projected life expectancy, and causes of death in a cohort of 2,574 patients who survived without recurrence of the original disease for at least 5 years after allogeneic or autologous hematopoietic cell transplantation from 1970 through 2002. Sex- and age-specific comparisons were made with US population data. Results Estimated survival of the cohort at 20 years after transplantation was 80.4% (95% CI, 78.1% to 82.6%). During 22,923 person-years of follow-up, 357 deaths occurred. Mortality rates remained four- to nine-fold higher than the expected population rate for at least 30 years after transplantation, yielding an estimated 30% lower life expectancy compared with that in the general population, regardless of current age. In rank order, the leading causes of excess deaths were second malignancies and recurrent disease, followed by infections, chronic graft-versus-host disease, respiratory diseases, and cardiovascular diseases. CONCLUSION Patients who have survived for at least 5 years after hematopoietic cell transplantation without recurrence of the original disease have a high probability of surviving for an additional 15 years, but life expectancy is not fully restored. Further effort is needed to reduce the burden of disease and treatment-related complications in this population.
This comparison of outcomes of allogeneic hematopoietic stem-cell transplantation in 1993–1997 and 2003–2007 shows that although patients had a somewhat poorer overall prognosis in the more recent ...period, the rate of death not preceded by relapse, the risk of relapse, and overall mortality decreased.
Infections, graft-versus-host disease (GVHD), and liver, kidney, and pulmonary complications have been associated with high mortality after allogeneic hematopoietic-cell transplantation since the introduction of this procedure 40 years ago.
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Changes in practice have decreased organ toxicity,
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and improved prevention and treatment strategies have decreased the severity of acute GVHD.
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The control of infectious complications has improved since the development of molecular methods for the detection of viral and fungal infections, the use of preemptive treatments, the introduction of new antifungal agents, and the prevention of nosocomial infection.
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To examine the hypothesis that changes in the care of . . .
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