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Targeted busulfan dosing helps limit chemotherapy-related toxicity and optimize disease outcomes in hematopoietic stem cell transplantation (HCT). The objective of this study was to evaluate busulfan exposure from a pharmacokinetic (PK)-guided dosing strategy using a test dose. This retrospective evaluation included adult patients who underwent HCT at our institution with busulfan-based myeloablative (>9 mg/kg) conditioning between January 2014 and October 2015. A weight-based test dose of 0.8 mg/kg was used with PK assessments to predict area under the curve (AUCpred) achieved with weight-based dosing, with a target AUC of 4800 µM*minute (AUCtarget). PK from the test dose was then used to calculate a PK-guided first myeloablative busulfan dose. PK assessments were also done after the first dose to assess if the goal area under the curve (AUC) had been achieved (AUCfirst). A PK-guided first dose resulted in achievement of target AUC with target ranges of ±10% in 50% of patients, ±15% in 75%, and ±20% in 94%. This was an improved rate of target achievement compared with the 33%, 44%, and 63% of patients who achieved the desired AUC for these respective target ranges when using weight-based dosing (P = .12, .004, and

Background Despite increasing donor options for allogeneic transplantation, including matched/mismatched related donors, matched unrelated donors and cord blood units, a proportion of patients do not find a donor. This is especially relevant in patients from racial/ethnic minorities. Post-transplant cyclophosphamide (PTCY) has successfully overcome barriers related to HLA-mismatching in the related donor setting. We hypothesized that transplantation with a mismatched unrelated donor (MMUD) using PTCY would be feasible and associated with high engraftment and acceptable GVHD incidence. Methods We performed a prospective Phase II study of MMUD bone marrow (BM) transplantation with PTCY for patients with hematologic malignancies. Patients with a suitable HLA matched related or URD were excluded. Patients received a fresh BM graft, followed by PTCY on days +3, +4, Sirolimus/MMF starting on Day+5. Matching for 4-7/8 at HLA-A, -B, -C, and –DRB1 was permitted. We enrolled 80 patients (40 full intensity conditioning [FIC]; 40 reduced intensity conditioning [RIC]) at 11 transplant centers in the U.S. between Dec 2016 and March 2019. Regimen intensity was at the center's discretion. Results Characteristics are shown in Table 1. Importantly, 48% of patients were non-white/Hispanic, 55% had an HCT-CI >2 and 34% had a KPS of 1 HLA allele, 59% were under 30. Overall survival and non-relapse mortality at 100 days were 92% and 5% in the FIC arm, and 90% and 7.5% in the RIC arm (Table 2). Neutrophil recovery was 98% in both arms, with no primary graft failure in the FIC arm, and 7.5% in the RIC arm. Peripheral blood donor chimerism was >75% at all timepoints. Acute GVHD grade III-IV at day 100 was relatively high at 25% in the FIC arm but very low at 2.6% in the RIC arm. Viral reactivations were high (Table 3). Conclusion These early (day 100) results of our prospective study show high rates of engraftment with acceptable rates of GVHD in recipients of MMUD transplantation with PTCY, despite a high degree of HLA mismatch. An important finding is that ethnic minorities represent almost 50% of the study population, showing that this approach expands access to patients in need of potentially curative therapy. BK and HHV-6 virus reactivation/infection were common, the clinical significance of which requires further study. Understanding the risks for and impact of graft failure and acute GVHD is being studied as follow up continues.

Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.

Autologous stem cell transplantation remains a mainstay of therapy for diseases such as multiple myeloma and relapsed lymphoma. The use of plerixafor has been shown to augment the ability to collect adequate stem cells, but the optimal use of this agent when used with chemotherapy is not yet clear. We utilized an algorithm-based approach with the addition of plerixafor to 54 patients undergoing chemomobilization with reduced-dose etoposide who had a less than optimal preapheresis CD34+ cell count. We used a CD34+ precount of 20 cells/μL as a threshold to initiate stem cell apheresis. Ninety-four percent of patients were successfully collected and proceeded to transplantation. Fourteen of 51 (28%) patients who successfully collected required plerixafor to augment stem cell yield. Of the patients who successfully collected, 94% (89% of the entire population) were able to collect in 2 or fewer days. Compared with previous data from our institution, the rate of patients collecting > 4 × 106 CD34+ cells/kg in a single collection was increased from 39% to 69%. The safety profile of this approach was acceptable. The use of this algorithm-based method to determine when and whether to add plerixafor to chemomobilization was shown to be a successful and cost-effective approach to stem cell collection.

Transplantation of one or two umbilical cord blood products is a useful alternative stem cell source. However, the limited number of stem cells in the infusion results in slow engraftment. In mouse models, administration of parathyroid hormone is an effective way to enhance the ability of limited numbers of hematopoietic stem cells to support hematopoiesis. In this study, patients received either a myeloablative or a reduced intensity double umbilical cord blood transplantation followed by parathyroid hormone at 100 μg daily for 28 days. Thirteen patients (median age 42 years) were enrolled. All patients engrafted; the median time to neutrophil and platelet engraftment >20x109 cells/L were 30 and 61 days respectively. The incidence of Grades II–IV acute GVHD was 38.5% at day 100. There were four deaths prior to Day 100, prompting early study closure. No patients receiving a myeloablative regimen relapsed. Overall survival at 6 months after transplantation was 62% and disease-free survival at 2 years was 39%. At the dose and schedule studied, there was no evidence that PTH influenced blood count recovery.

Purpose Event-free survival following all-trans-retinoic acid (ATRA) –based therapy for acute promyelocytic leukemia (APL) averages 70% at 5 years. While arsenic trioxide (ATO) can induce remissions in 95% of relapsed patients, few studies have addressed the integration of ATO into the primary management of APL. This study examines the efficacy of a single cycle of ATO-based consolidation therapy in a treatment regimen designed to decrease exposure to other cytotoxic agents. Patients and Methods After induction with ATRA and daunorubicin (DRN), untreated patients with APL received 3 days of cytarabine and DRN followed by 30 doses of ATO beginning on day 8. Molecular remitters received 2 years of risk-based maintenance therapy. Results Forty-one of 45 patients receiving induction therapy achieved remission; four patients died (one before treatment was initiated). Thirty-seven patients received consolidation and maintenance; of these one patient relapsed (CNS) and one died in remission during maintenance therapy (hepatic sickle cell crisis). With a median follow-up of 2.7 years, estimated disease-free survival was 90%; overall survival for all patients was 88%. Despite a total anthracycline dose of only 360 mg/m2, cardiac ejection fraction decreased by ≥ 20% in 20% of patients. Conclusion These data, combined with other recent studies using ATO in the primary management of APL, demonstrate the important role that ATO can play in the primary management of this curable disease. Future studies should continue to focus on reducing the toxicity of treatment without increasing the relapse rate.