Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis.

BACKGROUND: In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been a standard prophylaxis against graft-versus-host disease (GVHD). A phase 2 study indicated the potential superiority of a post-transplantation regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil. METHODS: In a phase 3 trial, we randomly assigned adults with hematologic cancers in a 1:1 ratio to receive cyclophosphamide-tacrolimus-mycophenolate mofetil (experimental prophylaxis) or tacrolimus-methotrexate (standard prophylaxis). The patients underwent HSCT from an HLA-matched related donor or a matched or 7/8 mismatched (i.e., mismatched at only one of the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci) unrelated donor, after reduced-intensity conditioning. The primary end point was GVHD-free, relapse-free survival at 1 year, assessed in a time-to-event analysis, with events defined as grade III or IV acute GVHD, chronic GVHD warranting systemic immunosuppression, disease relapse or progression, and death from any cause. RESULTS: In a multivariate Cox regression analysis, GVHD-free, relapse-free survival was significantly more common among the 214 patients in the experimental-prophylaxis group than among the 217 patients in the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P = 0.001). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups. CONCLUSIONS: Among patients undergoing allogeneic HLA-matched HSCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common among those who received cyclophosphamide-tacrolimus-mycophenolate mofetil than among those who received tacrolimus-methotrexate. (Funded by the National Heart, Lung, and Blood Institute and others; BMT CTN 1703 ClinicalTrials.gov number, NCT03959241.).

Early blood stream infection following allogeneic hematopoietic stem cell transplantation is a risk factor for acute grade III-IV GVHD in children and adolescents.

BACKGROUND: Graft-versus-host disease (GVHD) remains a major cause of mortality and morbidity in allogeneic hematopoietic stem cell transplantation (HSCT). In adults, early blood stream infection (BSI) and acute GVHD (AGVHD) have been reported to be related. The impact of BSI on risk for AGVHD, however, has not been assessed in pediatric patients. PROCEDURE: We conducted a retrospective analysis to test the hypothesis that early BSI (before day +30) predisposes allogeneic pediatric transplant patients to severe AGVHD. We analyzed 293 allogeneic HSCT performed at Children's Healthcare of Atlanta between 2005 and 2014 that met eligibility criteria. RESULTS: The cumulative incidence of acute grade III-IV GVHD at 100 days after HSCT was 17.1%. In multivariate analysis, risk for acute grade III-IV GVHD was associated with HLA-mismatched donor (hazard ratio [HR] = 4.870, P < 0.001), and BSI between day 0 and +30 prior to AGVHD (HR = 3.010, P = 0.001). CONCLUSIONS: These results indicate that early BSI appears to be a risk factor for acute grade III-IV GVHD. Further research is needed to determine if the link is causal.

African American Race Is a Newly Identified Risk Factor for Postengraftment Blood Stream Infections in Pediatric Allogeneic Blood and Marrow Transplantation.

Blood stream infections (BSI) are a major source of morbidity and mortality both in allogeneic blood and marrow transplant (BMT) recipients. Various risk factors for BSI in BMT have been identified. The impact of race and cytomegalovirus (CMV) viremia, a common complication after engraftment, however, has not been rigorously assessed. This is important because both CMV infection and ganciclovir, the mainstay of pre-emptive therapy, have myelosuppressive and immunosuppressive effects. We conducted a retrospective analysis to test the hypothesis that race and CMV viremia predispose allogeneic BMT patients to postengraftment BSI. We analyzed 278 allogeneic BMT performed at Children's Healthcare of Atlanta between January 1, 2005 and December 31, 2014 that met eligibility criteria. We performed a multivariate analysis to estimate the effect of CMV viremia on risk for BSI in the postengraftment period (days +30 to 100). Risk for BSI was associated with CMV viremia (hazard ratio [HR], 3.34; 95% confidence interval [CI], 1.51 to 7.36; P = .003); grade III and IV acute graft-versus-host disease (HR, 3.28; 95% CI, 1.55 to 6.92; P = .002), and African American race (HR, 2.22; 95% CI, 1.09 to 4.51; P = .027). The results of our study highlight the importance of a novel risk factor for postengraftment BSI, not previously considered-African American race.

Risk for CMV reactivation in children undergoing allogeneic hematopoietic stem cell transplantation.

Tailoring pre-emptive CMV therapy to hematopoietic cell transplant recipients' risk for reactivation could make this approach more cost-effective. To determine the feasibility of creating a risk classification system for this purpose, we analyzed 169 pediatric HCTs involving seropositive recipients or donors. Using risk factors derived from multivariable analysis, we stratified patients as having no risk factors, any one, any two, or all three risk factors (age, donor type, and presence of GVHD). The cumulative incidence of reactivation was 4.7%, 10.1%, 21.1%, and 40.9%, respectively (P ≤ 0.001). These results demonstrate the feasibility of creating a risk classification schema. Pediatr Blood Cancer 2015;62:364-366. © 2014 Wiley Periodicals, Inc.

Is the updated Schwartz formula appropriate for assessing renal function prior to hematopoietic stem cell transplantation?

Assessing renal function is an integral part of evaluating pediatric patients for hematopoietic stem cell transplantation (HSCT). The most accurate method is DTPA-Tc-(99m) GFR testing. However, it is costly and time consuming. The Schwartz formula, which was recently updated, represents an inexpensive and readily available alternative. We assessed agreement between the original and updated formula and DTPA-Tc-(99m) in 107 patients who were being evaluated for HSCT. Agreement between both formulas and DTPA-Tc-(99m) was poor, although the updated formula performed marginally better. The Schwartz formulas do not appear to be accurate enough to be used for pre-transplant kidney function evaluation.