Lowered-intensity preparative regimen for allogeneic stem cell transplantation delays acute graft-versus-host disease but does not improve outcome for advanced hematologic malignancy

AbstractReduced conditioning intensity has extended the option of allogeneic hematopoietic stem cell transplantation to patients who cannot tolerate fully myeloablative regimens. However, relapse and graft-versus-host disease (GVHD) continue to be major causes of morbidity and mortality. We prospectively tested whether a moderate reduction of the intensity of the preparative regimen would lead to significant reduction in regimen-related toxicity without compromising tumor control in a cohort of 44 patients ineligible for conventional hematopoietic stem cell transplantation. Patients were conditioned with fludarabine, busulfan, mycophenolate, and total lymphoid irradiation. Tacrolimus and methotrexate were given as prophylaxis for GVHD. Donors were 5 of 6 or 6 of 6 matched family members. The median age was 61 years. Eleven patients had comorbid conditions that precluded conventional myeloablative transplantation. Fatal regimen-related organ toxicity occurred in 3 patients. The cumulative incidence of grade 2 to 4 or grade 3 to 4 acute GVHD by day 100 was 38% (95% confidence interval [CI] = 25%, 55%) and 20% (95% CI = 10%, 39%), respectively, with a median time to onset of 66 days. For the entire cohort, 1-year overall survival, disease-free survival, and relapse rates were 54% (95% CI = 41%, 71%), 47% (95% CI = 35%, 65%), and 37% (95% CI = 19%, 51%), respectively. Outcomes differed based on stage of disease at time of transplantation, advanced (n = 19) versus nonadvanced (n = 25). Median survival times were 138 days and 685 days for subjects with advanced and nonadvanced disease, respectively (P = .005). After adjusting for age and comorbidity, disease stage continued to be significantly associated with overall survival (P = .005). In conclusion, a moderate reduction in conditioning dose intensity resulted in delayed onset of acute GVHD (compared with historical controls). A reduction in conditioning intensity is associated with poor survival for patients with advanced-stage disease, highlighting the importance of the conditioning regimen for tumor control. © 2003 American Society for Blood and Marrow TransplantationBiology of Blood and Marrow Transplantation 9:189-197 (2003

Liver Graft‐Versus‐Host Disease is associated with poor survival among allogeneic hematopoietic stem cell transplant recipients

Liver Graft‐versus‐host disease (GVHD) is common in patients with post‐transplant liver dysfunction following allogeneic hematopoietic stem cell transplantation (AHSCT). Oftentimes, the diagnosis is made clinically, and liver biopsy is deferred. Our objective was to evaluate the risk factors and clinical outcomes of liver GVHD among patients who developed post‐transplant liver dysfunction. Additionally, we evaluated the feasibility of liver biopsy in this population. We compared outcomes between liver GVHD and a “non‐liver GVHD” group, which consisted of other etiologies of post‐transplant liver dysfunction. Between January 2003 and December 2010, 249 patients developed post‐transplant liver dysfunction following AHSCT: 124 patients developed liver GVHD and 125 were in the “non‐liver GVHD” group. The incidence of acute and chronic liver GVHD at one year was 15.7% and 31.0%, respectively. The competing risk analysis revealed full intensity conditioning regimen (Hazard ratio [HR], 1.76; P = .008) and related donor (HR, 1.68; P = .004) as independent risk factors for liver GVHD. The time‐varying covariate Cox regression analysis with competing risk event, demonstrated that liver GVHD was independently associated with higher non‐relapse mortality, and adverse relapse‐free and overall survival. A total of 112 liver biopsies were performed in 100 patients. No major complications were observed. Liver biopsy confirmed prebiopsy hypotheses in 49% of cases, and led to treatment modification in 49% of patients. Our study shows that liver GVHD is associated with adverse survival. Liver biopsy is safe and often helps directing care in this setting.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151888/1/ajh25575.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151888/2/ajh25575_am.pd

Pilot Trial on the Use of Etanercept and Methylprednisolone as Primary Treatment for Acute Graft-versus-Host Disease

AbstractClinical and preclinical data indicate that tumor necrosis factor (TNF)–α is an important mediator of acute graft-versus-host disease (aGVHD) after allogeneic bone marrow transplantation. We completed a study using etanercept, a fusion protein capable of neutralizing TNF-α, for the initial treatment of aGVHD. Etanercept (25 mg subcutaneously) was administered twice weekly for 16 doses, along with methylprednisolone (2 mg/kg) and tacrolimus for biopsy-proven aGVHD. Twenty patients with a median age of 47 years (range, 8–63 years) were enrolled. Fourteen patients with grade II aGVHD (11 family donors and 3 unrelated donors) and 6 patients with grade III aGVHD (3 family donors and 3 unrelated donors) were treated. Twelve patients completed 16 doses of therapy, and 8 received 5 to 15 doses. Reasons for not completing all doses of etanercept included progression of aGVHD (n = 4), relapsed leukemia (n = 2), progression of pulmonary and central nervous system lesions (n = 1), and perforated duodenal ulcer (n = 1). Fifteen (75%) of 20 patients had complete resolution of aGVHD within 4 weeks of therapy. Increasing levels of soluble TNF receptor 1 plasma concentration during the first 4 weeks of therapy indicated progression of aGVHD in 5 patients. In contrast, for 15 responding patients, soluble TNF receptor 1 plasma concentration levels returned to baseline. These data demonstrate the feasibility of using cytokine blockade in the early treatment of aGVHD

Pathophysiology, prevention, and treatment of acute graft-versus-host disease

Abhinav Deol, Voravit Ratanatharathorn, Joseph P UbertiDepartment of Oncology, Blood and Marrow Stem Cell Transplant Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USAAbstract: Acute graft-versus-host disease (aGVHD) is an immunologically mediated inflammatory reaction, which continues to be a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplant. Although the occurrence and severity of this disease may be devastating, there is a proven immunologically mediated antitumor activity that accompanies the disease process, which has a beneficial effect on outcome. Animal models of graft-versus-host disease (GVHD) have given us a conceptual model that has allowed a better understanding of the pathophysiology and offers a framework for understanding the complex interactions between antigen-presenting cells, donor T-cells, and cytokines in the development of aGVHD. It has also given us a model that allows testing of various strategies for prevention and treatment. New, innovative approaches for treatment and prevention of aGVHD including better donor selection with the use of sophisticated human leukocyte antigen typing, use of T-cell depletion, reduced-intensity transplant regimens, and improved pharmacologic immunosuppression have improved outcomes by decreasing the incidence and severity of aGVHD. However, the limitation of these strategies is that effective treatment and prevention of aGVHD is often accompanied by a concomitant rise in relapses, graft failure and infections, and ultimately no improvement in overall survival. Investigators are working on understanding the difference between GVHD and graft versus tumor effect, as this would be the key in improving outcomes for our patients. In this review, we will discuss the pathophysiology of aGVHD along with the preventative and treatment strategies.Keywords: acute GVHD, GVHD, acute graft-versus-host disease, bone marrow transplan

Driving Distance and Patient-Reported Outcomes in Hematopoietic Cell Transplantation Survivors.

Long driving distances to transplantation centers may impede access to care for hematopoietic cell transplantation (HCT) survivors. As a secondary analysis from the multicenter INSPIRE study (NCT01602211), we examined baseline data from relapse-free HCT adult survivors (2 to 10 years after allogeneic or autologous HCT) to investigate the association between driving distances and patient-reported outcome (PRO) measures of distress and physical function. We analyzed predictors of elevated distress and impaired physical function using logistic regression models that operationalized driving distance first as a continuous variable and separately as a dichotomous variable (<100 versus 100+ miles). Of 1136 patients available for analysis from 6 US centers, median driving distance was 82 miles and 44% resided 100+ miles away from their HCT centers. Elevated distress was reported by 32% of patients, impaired physical function by 19%, and both by 12%. Driving distance, whether operationalized as a continuous or dichotomous variable, had no impact on distress or physical function in linear regression modeling (95% confidence interval, 1.00 to 1.00, for both PROs with driving distance as a continuous variable). In contrast, chronic graft-versus-host-disease, lower income, and lack of Internet access independently predicted both elevated distress and impaired physical function. In summary, we found no impact of driving distance on distress and physical function among HCT survivors. Our results have implications for how long-term follow-up care is delivered after HCT, with regard to the negligible impact of driving distances on PROs and also the risk of a "digital divide" worsening outcomes among HCT survivors without Internet access