Donor-Host Lineage-Specific Chimerism Monitoring and Analysis in Pediatric Patients Following Allogeneic Stem Cell Transplantation: Influence of Pretransplantation Variables and Correlation with Post-Transplantation Outcomes.

The impact of donor-host chimerism in post-hematopoietic stem cell transplantation (HSCT) outcomes is poorly understood. We were interested in studying whether pre-HSCT variables influenced lineage-specific donor-host chimerism and how lineage-specific chimerism impacts post-HSCT outcomes. Our main objective was to study pre-HSCT variables as predictors of lineage-specific donor-host chimerism patterns and to better characterize the relationship between post-HSCT lineage-specific chimerism and adverse outcomes, including graft failure and disease relapse. We conducted a retrospective data analysis of all patients who underwent allogeneic HSCT at the Pediatric Transplantation and Cellular Therapy service at Memorial Sloan Kettering Cancer Center between January 2010 and June 2015 and had at least 2 measurements of split-lineage chimerism. The trend of lineage-specific donor-host chimerism post-HSCT and the impact of age, disease, graft type, and pretransplantation conditioning regimen on chimerism at 3 months and 12 months post-HSCT were studied. The Wilcoxon signed-rank test, Mann-Whitney-Wilcoxon test, and Cox proportional hazard models were used for statistical analyses. A total of 137 patients were included (median age, 11.3 years). Most patients had a hematologic malignancy (n = 95), and fewer had a nonmalignant disorder (n = 27) or primary immune deficiency (n = 15). Myeloablative conditioning regimens (n = 126) followed by T cell-depleted (TCD) peripheral blood stem cell or bone marrow grafts (n = 101) were most commonly used. Mixed chimerism (MC) of total peripheral blood leukocytes (PBLs) did not predict loss of donor chimerism in all lineages and when stable was not associated with graft failure or rejection in this analyses. Split chimerism with complete donor chimerism (CC) of myeloid, B, and natural killer cells, but not T cells, occurred early post-HSCT, but full donor T cell chimerism was achieved at 12 months post-HSCT by most patients. MC within the T cell lineage was the major contributor to PBL MC, with lower median donor T cell chimerism at 3 months than at 12 months (91%) post-HSCT (51% versus 91%; P < .0001). Predictors of MC at 3 and 12 months were (1) age <3 years (P = .01 for PBLs and P = .003 for myeloid lineage); (2) nonmalignant disorder (P = .007 for PBLs); and (3) the use of reduced-intensity conditioning regimens. TCD grafts produced lower donor T cell chimerism at 3 months post-HSCT compared with unmodified grafts (P < .0001), where T cell lineage CC was achieved early post-HSCT. The donor T cell chimerism was similar at 12 months in the 2 types of grafts. Umbilical cord blood grafts had CC in all lineages at all time points post-HSCT. Loss of donor B cell chimerism was associated with increased risk of relapse in hematologic malignancies (hazard ratio, 1.33; P = .05). Age, underlying disease, conditioning regimen, and graft manipulation can impact post-HSCT donor-host chimerism and be predictors for early MC. MC in total PBLs and T cells was not related to graft failure or disease relapse. Whole-blood PBL chimerism analysis is not sufficient to assess the significance of post-HSCT donor-host status; rather, lineage-specific chimerism, particularly for myeloid, T, and B cells, should be analyzed to guide interventions and inform outcomes.

Busulfan Pharmacokinetics and Precision Dosing: Are Patients with Fanconi Anemia Different?

It is well known that pharmacokinetics (PK)-guided busulfan (BU) dosing increases engraftment rates and lowers hepatotoxicity in patients undergoing hematopoietic cell transplantation (HCT). However, there are no published PK data in patients with Fanconi anemia (FA), who are known to have baseline DNA repair defect and related inherent sensitivity to chemotherapy. In our prospective, multi-institutional study of alternative donor HCT for FA using chemotherapy-only conditioning, we replaced the single dose of total-body irradiation with BU at initial doses of 0.8 to 1.0 mg/kg and 0.6 to 0.8 mg/kg given i.v. every 12 hours for 4 doses. Patients received the first dose of i.v. busulfan on day -8, and blood levels for PK were obtained. PK samples were drawn following completion of infusion. BU PK levels were collected at 2 hours, 2 hours and 15 minutes, and 4, 5, 6, and 8 hours from the start of infusion. The remaining 3 doses of BU were given on days -7 and -6. Thirty-seven patients with available BU PK data with a median age of 9.2 years (range, 4.3 to 44 years) are included in the final analyses. The overall BU PK profile in patients with FA is similar to non-FA patients after considering their body weight. In our cohort, a strong correlation between BU clearance and weight supports current practice of per kilogram dosing. However, not surprisingly, we show that the disease (ie, host) sensitivity related to FA is the main determinant of total dose of BU that can be safely administered to patients in this high-risk population. On the basis of our results, we propose an optimal BU concentration at steady-state level of ≤350 ng/mL (equivalent to total cumulative exposure of 16.4 mg*h/L for 4 doses over 2 days) for patients with FA undergoing HCT. To our knowledge, this is the first and largest report of prospective BU PK in patients with FA undergoing HCT, providing an optimal BU target cutoff to achieve stable donor engraftment while avoiding excessive toxicity.

A Chemotherapy-Only Regimen of Busulfan, Melphalan, and Fludarabine, and Rabbit Antithymocyte Globulin Followed by Allogeneic T-Cell Depleted Hematopoietic Stem Cell Transplantations for the Treatment of Myeloid Malignancies.

We sought to develop a myeloablative chemotherapeutic regimen to secure consistent engraftment of T-cell depleted (TCD) hematopoietic stem cell transplantations (HSCT) without the need for total body irradiation, thereby reducing toxicity while maintaining low rates of graft-versus-host disease (GVHD) and without increasing relapse. We investigated the myeloablative combination of busulfan (Bu) and melphalan (Mel), with the immunosuppressive agents fludarabine (Flu) and rabbit antithymocyte globulin (r-ATG) as cytoreduction before a TCD HSCT. No post-transplantation immunosuppression was administered. Between April 2001 and May 2008, 102 patients (median age, 55 years) with a diagnosis of primary or secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) underwent cytoreduction with Bu/Mel/Flu, followed by TCD grafts. TCD was accomplished by CD34+-selection followed by E-rosette depletion for peripheral blood stem cell grafts and, for bone marrow grafts, by soybean agglutination followed by E-rosette depletion. Donors included matched and mismatched, related and unrelated donors. Risk stratification was by American Society for Blood and Marrow Transplantation risk categorization for patients with primary disease. For patients with secondary/treatment-related MDS/AML, those in complete remission (CR) 1 or with refractory anemia were classified as intermediate risk, and all other patients were considered high risk. Neutrophil engraftment occurred at a median of 11 days in 100 of 101 evaluable patients. The cumulative incidences of grades II to IV acute and chronic GVHD at 1 year were 8.8% and 5.9%, respectively. Overall- and disease-free survival (DFS) rates at 5 years were 50.0% and 46.1%, respectively, and the cumulative incidences of relapse and treatment-related mortality were 23.5% and 28.4%, respectively. Stratification by risk group demonstrated superior DFS for low-risk patients (61.5% at 5 years) compared with intermediate- or high-risk (34.2% and 40.0%, respectively, P = .021). For patients with AML, those in CR1 had superior 5-year DFS compared with those in ≥CR2 (60% and 30.6%, respectively, P = .01), without a significant difference in incidence of relapse (17.1% and 30.6%, respectively, P = .209). There were no differences in DFS for other patient, donor, or disease characteristics. In summary, cytoreduction with Bu/Mel/Flu and r-ATG secured consistent engraftment of TCD transplantations. The incidences of acute/chronic GVHD and disease relapse were low, with favorable outcomes in this patient population with high-risk myeloid malignancies.

Factors Associated With Participation in an Emergency Department-Based Take-Home Naloxone Program for At-Risk Opioid Users.

STUDY OBJECTIVE: Although the World Health Organization recommends take-home naloxone to address the increasing global burden of opioid-related deaths, few emergency departments (EDs) offer a take-home naloxone program. We seek to determine the take-home naloxone acceptance rate among ED patients at high risk of opioid overdose and to examine factors associated with acceptance. METHODS: At a single urban ED, consecutive eligible patients at risk of opioid overdose were invited to complete a survey about opioid use, overdose experience, and take-home naloxone awareness, and then offered take-home naloxone. The primary outcome was acceptance of take-home naloxone, including the kit and standardized patient training. Univariate and multivariable logistic analyses were used to evaluate factors associated with acceptance. RESULTS: Of 241 eligible patients approached, 201 (83.4%) completed the questionnaire. Three-quarters of respondents used injection drugs, 37% were women, and 26% identified as "Indigenous." Of 201 respondents, 137 (68.2%; 95% confidence interval [CI] 61.7% to 74.7%) accepted take-home naloxone. Multivariable analysis revealed that factors associated with take-home naloxone acceptance included witnessing overdose in others (odds ratio [OR] 4.77; 95% CI 2.25 to 10.09), concern about own overdose death (OR 3.71; 95% CI 1.34 to 10.23), female sex (OR 2.50; 95% CI 1.21 to 5.17), and injection drug use (OR 2.22; 95% CI 1.06 to 4.67). CONCLUSION: A two-thirds ED take-home naloxone acceptance rate in patients using opioids should encourage all EDs to dispense take-home naloxone. ED-based take-home naloxone programs have the potential to improve access to take-home naloxone and awareness in individuals most vulnerable to overdoses.