Evaluation of a Test Dose Strategy for Pharmacokinetically-Guided Busulfan Dosing for Hematopoietic Stem Cell Transplantation

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 (AUC_pred) achieved with weight-based dosing, with a target AUC of 4800 µM*minute (AUC_target). 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 (AUC_first). 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 <.001, respectively). The PK-guided strategy also decreased the variability of AUC from 3.6-fold in AUC_pred from the weight-based test doses (2700.8 to 9631 µM*minute; SD, 1211.6 µM*minute) to 1.8-fold in AUC_first from the PK-guided first doses (3672.1 to 6609.8 µM*minute; SD, 574.7 µM*minute). This reflects a 2-fold improvement in AUC variability with a PK-guided dosing strategy. This is also improved from the 3-fold variability in AUC reported in other studies. Weight and body surface area were significantly associated with the likelihood of AUC_first being within the ±10% target range (P?=?.04 for both associations). There was no significant association between AUC_first and death, relapse, or a composite of the two. These results demonstrate a significant improvement in target AUC attainment and less interpatient variability with PK-guided dosing using a test dose strategy compared with weight-based dosing.     

Thiotepa,Busulfan, and Fludarabine Conditioning Regimen in T Cell-Replete HLA-Haploidentical Hematopoietic Stem Cell Transplantation

We report the outcomes of 51 patients who underwent unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation cyclophosphamide (PT-Cy) and antithymocyte globulin (ATG), from peripheral blood stem cells (PBSCs) or bone marrow, after receipt of a TBF (thiotepa, busulfan, and fludarabine) conditioning regimen. Their median age was 55 years (range, 16 to 72 years). Hematologic diagnoses included acute leukemias (n = 31), lymphoid neoplasm (n = 12), myeloproliferative neoplasm (n = 5), and myelodysplastic syndromes (n = 3). Thirty-seven patients (73%) were in complete remission. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate for all patients, associated with ATG in 39 patients (76.5%). The median time to neutrophil engraftment was 17 days (range, 12 to 34 days). The cumulative incidences of grade II-IV and grade III-IV acute GVHD were 27.5% and 14%, respectively. In patients receiving a PBSC graft and ATG prophylaxis, grade II-IV aGVHD occurred in 16% of patients. The use of ATG and a lower thiotepa dose (5 mg/kg versus 10 mg/kg) were associated with a reduced cumulative incidence of grade II-IV acute GVHD (P = .03 and .005, respectively). The 2-year cumulative incidence of chronic GVHD was 29% and was significantly reduced to 13% with the lower thiotepa dose (P = .002). After a median follow-up of 25 months (range, 12 to 62 months), the cumulative incidences of nonrelapse mortality, relapse, overall survival (OS), disease-free survival (DFS), and GVHD-free, relapse-free survival (GFRFS) were 20%, 22.5%, 67%, 58%, and 51%, respectively. Pretransplantation disease status (complete remission versus others) was the main factor associated with OS, DFS, and GFRFS. In conclusion, the TBF conditioning regimen is an appealing platform in the haplo-HSCT setting with PT-Cy in terms of engraftment rate, toxicity, and disease control. We found no benefit of a thiotepa dose of 10 mg/kg compared with a dose of 5 mg/kg. ATG reduced the risk of acute GVHD without comprising outcomes.     

Pulmonary Hypertension after Hematopoietic Stem Cell Transplantation

Pulmonary hypertension (PH) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). Given its nonspecific clinical presentation, it is likely that this clinical entity is underdiagnosed after HSCT. Data describing the incidence, risk factors, and etiology of PH in HSCT recipients are minimal. Physicians caring for HSCT recipients should be aware of this severe post-transplant complication because timely diagnosis and treatment may allow improved clinical outcomes. We summarize the pathophysiology, clinical presentation, diagnosis, and management of PH in HSCT recipients.     

Hematopoietic Stem Cell Transplantation for Shwachman-Diamond Syndrome

We report the outcomes of hematopoietic stem cell transplantation (HSCT) for 52 patients with Shwachman-Diamond syndrome (SDS) who underwent transplantation between 2000 and 2017. The median age at transplantation was 11 years, and the median duration of follow-up was 60 months. The indication for HSCT was bone marrow failure (BMF; cytopenia or aplastic anemia) in 39 patients and myelodysplasia (MDS)/acute myelogenous leukemia (AML) in 13 patients. The donor type was an HLA-matched sibling for 18 patients, an HLA-matched or mismatched relative for 6 patients, and an HLA-matched or mismatched unrelated donor for 28 patients. Preparative regimens for BMF were myeloablative in 13 patients and reduced intensity in 26. At the time of this report, 29 of the 39 patients with BMF were alive, and the 5-year overall survival was 72% (95% confidence interval, 57% to 86%). Graft failure and graft-versus-host disease were the predominant causes of death. Preparative regimens for patients with MDS/AML were myeloablative in 8 and reduced intensity in 5. At the time of this report, only 2 of 13 patients were alive (15%), with relapse the predominant cause of death. Survival after transplantation for SDS-related BMF is better compared with historical reports, but strategies are needed to overcome graft failure and graft-versus-host disease. For SDS- related MDS or AML, transplantation does not extend survival. Rigorous surveillance and novel treatments for leukemia are urgently needed.     

Hematopoietic Stem Cell Transplantation and Hematopoietic Stem Cell Gene Therapy in X‐Linked Adrenoleukodystrophy

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only therapeutic approach that can arrest cerebral demyelination of X‐linked adrenoleukodystrophy (ALD) in boys and results in long‐term in a good quality of life, provided the procedure is performed at an early stage of disease. Similar benefits of allogeneic HSCT have been demonstrated in adults with cerebral ALD. However, it is not yet known whether allogeneic HSCT can prevent or rescue adrenomyeloneuropathy. Allogeneic HSCT remains associated with significant morbidity and mortality risks, particularly in adults, and not all ALD patients have donors despite the availability of cord blood. The absence of biological markers that can predict the evolutivity of cerebral disease is a major limitation to propose in due time allogeneic HSCT to ALD patients. Recently, HSC gene therapy using lentiviral vector was shown to have comparable efficacy than allogeneic HSCT in two boys with cerebral ALD who had no Human‐leukocyte‐antigen (HLA)‐matched donor. If these results are confirmed in an extended series of patients, HSC gene therapy may become the first therapeutic option for all ALD male patients who develop cerebral demyelination.     

Outcomes of Lung Transplantation after Allogeneic Hematopoietic Stem Cell Transplantation

Other than lung transplantation (LT), no specific therapies exist for end-stage lung disease resulting from hematopoietic stem cell transplantation (HCT)-related complications, such as bronchiolitis obliterans syndrome (BOS). We report the indications and outcomes in patients who underwent LT after HCT for hematologic disease from a retrospective case series at our institution and a review of the medical literature. We identified a total of 70 cases of LT after HCT, including 9 allogeneic HCT recipients from our institution who underwent LT between 1990 and 2010. In our cohort, the median age was 16 years (range, 10 to 35 years) at the time of HCT and 34 years (range, 17 to 44 years) at the time of LT, with a median interval between HCT and LT of 10 years (range, 2.9 to 27 years). Indications for LT-included pulmonary fibrosis (n = 4), BOS (n = 3), interstitial pneumonitis related to graft-versus-host disease (GVHD) (n = 1), and primary pulmonary hypertension (n = 1). Median survival was 49 months (range, 2 weeks to 87 months), and 1 patient remains alive at more than 3 years after LT. Survival at 1 year and 5 years after LT was 89% and 37%, respectively. In the medical literature between 1992 and July 2013, we identified 20 articles describing 61 cases of LT after HCT from various centers in the United States, Europe, and Asia. Twenty-six of the 61 cases (43%) involved patients age <18 years at the time of LT. BOS and GVHD of the lung were cited as the indication for LT in the majority of cases (80%; n = 49), followed by pulmonary fibrosis and interstitial lung disease (20%; n = 12). In publications reporting 3 or more cases with a follow-up interval ranging from the immediate postoperative period to 16 years, the survival rate was 71% (39 of 55). Most deaths were attributed to long-term complications of the lung allograft, including infections and BOS. Two deaths were related to recurrent or relapsed hematologic malignancy. LT can prolong survival in some patients who suffer from end-stage pulmonary complications after HCT. Patient factors that likely improve the chances of a good long-term outcome include young age, at least 2 years post-HCT free of relapse from the original hematologic malignancy, and lack of other end-organ dysfunction or manifestations of chronic GVHD that require treatment with immunosuppressive agents.     

Immune Reconstitution after Haploidentical Hematopoietic Stem Cell Transplantation

Haploidentical hematopoietic stem cell transplantation (HSCT) offers the benefits of rapid and nearly universal donor availability and has been accepted worldwide as an alternative treatment for patients with hematologic malignancies who do not have a completely HLA-matched sibling or who require urgent transplantation. Unfortunately, serious infections and leukemia relapse resulting from slow immune reconstitution remain the 2 most frequent causes of mortality in patients undergoing haploidentical HSCT, particularly in those receiving extensively T cell–depleted megadose CD34⁺ allografts. This review summarizes advances in immune recovery after haploidentical HSCT, focusing on the immune subsets likely to have the greatest impact on clinical outcomes. The progress made in accelerating immune reconstitution using different strategies after haploidentical HSCT is also discussed. It is our belief that a predictive immune subset–guided strategy to improve immune recovery might represent a future clinical direction.     

Hematopoietic Stem Cell Transplantation for XIAP Deficiency in Japan

Background

X-linked inhibitor of apoptosis protein (XIAP) deficiency is a rare immunodeficiency that is characterized by recurrent hemophagocytic lymphohistiocytosis (HLH) and splenomegaly and sometimes associated with refractory inflammatory bowel disease (IBD). Although hematopoietic stem cell transplantation (HSCT) is the only curative therapy, the outcomes of HSCT for XIAP deficiency remain unsatisfactory compared with those for SLAM-associated protein deficiency and familial HLH.

Aim

To investigate the outcomes and adverse events of HSCT for patients with XIAP deficiency, a national survey was conducted.

Methods

A spreadsheet questionnaire was sent to physicians who had provided HSCT treatment for patients with XIAP deficiency in Japan.

Results

Up to the end of September 2016, 10 patients with XIAP deficiency had undergone HSCT in Japan, 9 of whom (90%) had survived. All surviving patients had received a fludarabine-based reduced intensity conditioning (RIC) regimen. Although 5 patients developed post-HSCT HLH, 4 of them survived after etoposide administration. In addition, the IBD associated with XIAP deficiency improved remarkably after HSCT in all affected cases.

Conclusion

The RIC regimen and HLH control might be important factors for successful HSCT outcomes, with improved IBD, in patients with XIAP deficiency.

     

Hematopoietic Stem Cell Transplantation in Patients Infected With HIV

Hematopoietic stem cell transplantation (HSCT) replaces a diseased hematopoietic system with a functional, disease-free graft and is frequently used in the treatment of hematologic malignancies. The advent of highly active antiretroviral therapy made it possible to treat medical conditions in HIV-infected patients in the same way as in the general population. Several studies have reported the feasibility, safety, and efficacy of autologous HSCT as rescue or consolidation treatment for non-Hodgkin’s and Hodgkin’s lymphoma in HIV-infected patients. As a result of the improvements in supportive care and the introduction of attenuated transplant conditioning regimens, allogeneic HSCT has been used to treat life-threatening hematologic disorders, with promising results in HIV-infected patients. Moreover, this strategy has made it possible to treat both the hematologic disease and HIV infection.     

Inflammatory Markers in Patients after Hematopoietic Stem Cell Transplantation

Infections are one of the most common complications after hematopoietic stem cell transplantation (HSCT). Diagnosis is established by analysis of clinical symptoms and results of diagnostic tests such as biochemical panels, microbiological cultures, and visual diagnostics. As the microbiological cultures yield positive results in only some patients and visual diagnostics might miss the infectious source, the diagnosis and proper treatment often depends on clinical assessment supported by laboratory test results. The most commonly used makers of inflammation include C-reactive protein and procalcitonin. However, these tests have serious limitations when used in patients after HSCT. The drugs used in conditioning, neutropenia, and graft-versus-host disease might influence the results of the tests and misguide the physician. In this review, we summarize the current knowledge on profiles of expression of basic markers of inflammation used in clinical practice in patients after HSCT.     

Autologous Hematopoietic Stem Cell Transplantation in Acute Myelogenous Leukemia

The clinical outcomes of autologous hematopoietic stem cell transplantation (ASCT) in acute myelogenous leukemia (AML) have improved over time. Indeed, numerous studies have demonstrated that ASCT is associated with a lower relapse rate and acceptable nonrelapse mortality compared with chemotherapy alone in patients with AML. In addition, ASCT is also associated with comparable overall survival outcomes to those of allogeneic hematopoietic stem cell transplantation in some patients with AML. To date, age, cytogenetic and molecular risk stratification, and minimal residual disease (MRD) status have been shown to be closely related to clinical outcomes following ASCT. ASCT is recommended for patients with favorable-risk and intermediate-risk AML in first complete remission and patients with acute promyelocytic leukemia in second complete remission for whom a matched sibling donor is not available. MRD status pre-ASCT is the most important factor to consider when determining whether a patient is eligible for ASCT and can effectively predict clinical outcomes after ASCT. Advanced age is not an absolute contradiction for ASCT. In this review, we describe the literature and clinical trials evaluating the outcomes of ASCT in patients with AML and discuss the indications for ASCT therapy. Because the greatest concern in ASCT recipients is early relapse, important factors that should be monitored before ASCT and future perspectives in this area are also presented.     

Association between Busulfan Exposure and Outcome in Children Receiving Intravenous Busulfan before Hematologic Stem Cell Transplantation

Busulfan, combined with therapeutic drug monitoring–guided dosing, is associated with higher event-free survival (EFS) rates due to fewer graft failures/relapses and lower toxicity. The optimal target area under the curve (AUC) and dosing schedule of intravenous busulfan in children undergoing hematopoietic stem cell transplantation (HSCT) remain unclear, however. We conducted a retrospective analysis of the association between busulfan exposure and clinical outcome in 102 children age 0.2 to 21 years who received busulfan 1 or 4 times daily before undergoing HSCT (46 malignant and 56 nonmalignant indications). EFS and overall survival after a median of 2 years of follow-up were 68% and 72%, respectively. EFS was optimal when the exposure of busulfan (AUC) was 78 mg1h/L (95% confidence interval = 74 to 82 mg1h/L). Acute graft-versus-host disease (aGVHD) grade II–IV occurred more frequently with greater busulfan exposure. The addition of melphalan was an independent risk factor; melphalan use combined with high busulfan exposure (AUC > 74 mg1h/L) was associated with high incidences of aGVHD (58%), veno-occlusive disease (66%), and mucositis grade III-IV (26%). Dosing frequency (1 or 4 times daily) was not related to any outcome. In conclusion, dose targeting of busulfan to a narrow therapeutic range was found to increase EFS in children. Adding melphalan to optimal busulfan exposure is associated with a high incidence of toxicity.     

Comparison of Intravenous with Oral Busulfan in Allogeneic Hematopoietic Stem Cell Transplantation with Myeloablative Conditioning Regimens for Pediatric Acute Leukemia

Recent reports revealed that intravenous (iv) busulfan (BU) may not only reduce early nonrelapse mortality (NRM) but also improve overall survival (OS) probability in adults. Therefore, we retrospectively compared outcomes for 460 children with acute leukemia who underwent hematopoietic stem cell transplantation with either iv-BU (n = 198) or oral busulfan (oral-BU) (n = 262) myeloablative conditioning. OS at 3 years was 53.4% ± 3.7% with iv-BU and 55.1% ± 3.1% with oral-BU; the difference was not statistically significant (P = .77). OS at 3 years in 241 acute lymphoblastic leukemia and 219 acute myeloid leukemia patients was 56.4% ± 5.5% with iv-BU and 54.6% ± 4.1 with oral-BU (P = .51) and 51.0% ± 5.0% with iv-BU and 55.8% ± 4.8% with oral-BU (P = .83), respectively. Cumulative incidence of relapse at 3 years with iv-BU was similar to that with oral-BU (39.0% ± 3.6% and 36.4% ± 3.1%, respectively; P = .67). Cumulative incidence of NRM at 3 years was 16.6% ± 2.7% with iv-BU and 18.3% ± 2.5% with oral-BU (P = .51). Furthermore, multivariate analysis showed no significant survival advantage with iv-BU. In conclusion, iv-BU failed to show a significant survival advantage in children with acute leukemia.