Biology of Blood and Marrow Transplantation最新文献

Allogeneic hematopoietic cell transplantation (HCT) is the treatment of choice for acute myelogenous leukemia (AML) not responding to induction therapy. It is a therapeutic choice for the blast phase of chronic myelogenous leukemia (CML-BP) in patients failing to respond to tyrosine kinase inhibitors (TKIs). Lipid core nanoparticles (LDEs) concentrate severalfold more in blast cells than in corresponding normal cells. Incorporation of anticancer drugs to LDE formulations increases the pharmacologic action and decreases the toxicity. We tested a drug-targeting system, LDE-etoposide plus total body irradiation (TBI; 1200 cGy dose), in 13 patients with AML not responding to the induction therapy and in 2 patients with CML-BP refractory to second-generation TKIs. The mean patient age was 46.7 years (range, 22 to 66 years). The LDE-etoposide dose was escalated at 20, 30, 40, 50, and 60 mg/kg. No patients developed grade 4 or 5 toxicity; however, mucositis grade 3 occurred in 6 patients, 3 patients experienced diarrhea, and 1 patient had an elevated total bilirubin level. No deaths were related to conditioning. All patients were successfully engrafted. The median times to neutrophil and platelet engraftment were 20 ± 5 days and 16 ± 4 days, respectively. Five patients (33.4%) had acute graft-versus-host-disease (GVHD), including 4 grade I, and 1 with grade II, and 8 patients (57.1%) had moderate-to-severe chronic GVHD. This pilot study shows the potential of LDE-etoposide plus TBI as an HCT conditioning regimen in AML patients not responding to the induction and refractory therapies for CML-BP patient. These findings pave the way for subsequent larger clinical trials.

Relapse is a major concern with reduced-intensity conditioning. We analyzed 257 patients with acute myeloid leukemia (AML) who received allogeneic stem cell transplantation (SCT) and fulfilled the following criteria: intermediate- or poor-risk disease by National Comprehensive Cancer Network guidelines (2017, version 3), in first complete remission (CR1) at SCT, received either myeloablative conditioning (MAC; busulfan plus cyclophosphamide or cyclophosphamide plus total body irradiation) or reduced-intensity conditioning (RIC; FluBu2TBI400) peripheral blood SCT from 8/8 matched sibling or unrelated donor, and having bone marrow Wilms tumor gene 1 (WT1) expression results before transplant. We and other groups serially published a predictive value for pretransplant WT1 expression in patients with AML to identify patients at higher risk of relapse. Among the total 257 patients, 191 (74.3%) and 66 (25.7%) patients received MAC and RIC transplants, respectively. WT1 ≥250 copies/10⁴ ABL was defined as WT1^high. WT1^high before SCT was found to be an independent prognostic factor for inferior overall survival (OS), disease-free survival (DFS), and higher cumulative incidence of relapse (CIR). There were 201 patients with WT1 low expression based upon pretransplant analysis. There was no significant difference in OS, DFS, CIR, and nonrelapse mortality between MAC and RIC patients. To conclude, post-transplant survival or relapse was not different by conditioning intensity in AML CR1 patients whose WT1 level was below 250 copies per 10⁴ ABL at transplantation.

There is a paucity of information about nutrition in chronic graft-versus-host disease (GVHD). The role of nutrition is important because malnutrition is strongly associated with severe chronic GVHD manifestations. There is a high prevalence of metabolic syndrome and osteoporosis in this setting. Here we review the literature, describe main aspects of nutrition and discuss macronutrients (ie, vitamins), micronutrients (ie, Mg, Zn, Ca, and K) and supplements (probiotics and omega 3 fatty acids). A search was carried out in March 2020 using PubMed. Databases were screened for searching terms in titles and abstracts referring to chronic GVHD, nutrition intervention, protein, and body composition. Data were extracted for the following outcomes: nutrition, nutrition intervention, chronic GVHD, nutrition deficiencies, diet, vitamin, dry eye, probiotic, protein, and body composition. In this report, we summarize interventional nutrition studies reported in oncology and metabolic syndrome settings and describe our nutritional clinical practice in hematopoietic cell transplantation and chronic GVHD. The impact of nutrition evaluation and intervention on muscle mass loss, dry eye, dysgeusia, metabolic syndrome, osteoporosis, and comorbidities associated with chronic GVHD need to be studied prospectively.

The use of myeloablative conditioning (MAC) in the setting of active relapsed/refractory (R/R) acute myeloid leukemia (AML) has been hindered by high historical rates of nonrelapse mortality (NRM). FLAMSA (fludarabine, Ara-C, and amsacrine) chemotherapy (CT) followed by reduced-intensity conditioning (RIC) has been proposed as an effective and potentially safer alternative in this scenario. As improvements in supportive care have contributed to decreasing NRM rates after MAC, a comparative reassessment of these two strategies was performed. This was a registry-based analysis by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Eligibility criteria included age 18 to 50 years, primary refractory, first or second relapsed active AML, first allogeneic stem cell transplantation from a matched sibling donor (MSD) or an unrelated donor (UD) performed between 2005 and 2018, MAC or FLAMSA-RIC. A total of 1018 patients were included. The median patient age was 39 years (range, 18 to 50). Two hundred and fifty-eight patients received busulfan (Bu)/cyclophosphamide (Cy), 314 received Cy/total body irradiation (TBI), 318 received FLAMSA-TBI, and 128 received FLAMSA-CT. The median duration of follow-up was 50 months. In univariate analysis, the 2-year relapse incidence (RI) (54%; 95% confidence interval (CI), 50%-57%), leukemia-free survival (LFS) (30%; 95% CI, 27%-33%), and refined graft-versus-host disease-free, relapse-free survival (GRFS) (21%; 95% CI, 18%-24%) were not significantly different between cohorts. Lower 2-year NRM was observed in the FLAMSA-CT group (7% versus 16% in Bu/Cy, 19% in Cy/TBI, and 18% in FLAMSA-TBI; P = .04), as well as increased 2-year overall survival (OS) (50% versus 33% in Bu/Cy, 34% in Cy/TBI, and 36% in FLAMSA-TBI; P = .03). These results were maintained in the multivariate analysis (hazard ratio [HR] for NRM: .40, P = .01; HR for OS: .65, P = .01; Bu/Cy as reference). These data suggest that FLAMSA-CT may be a preferred conditioning regimen in patients with active R/R AML due to lower NRM. Yet, the high relapse rates observed in our analyses emphasize the need for novel therapeutic strategies in this clinical setting.

Allogeneic hematopoietic cell transplantation (alloHCT) for multiple myeloma (MM), with its underlying graft-versus-tumor capacity, is a potentially curative approach for high-risk patients. Relapse is the main cause of treatment failure, but predictors for postrelapse survival are not well characterized. We conducted a retrospective analysis to evaluate predictors for postrelapse overall survival (OS) in 60 MM patients who progressed after myeloablative T cell-depleted alloHCT. The median patient age was 56 years, and 82% had high-risk cytogenetics. Patients received a median of 4 lines of therapy pre-HCT, and 88% achieved at least a partial response (PR) before alloHCT. Of the 38% who received preemptive post-HCT therapy, 13 received donor lymphocyte infusions (DLIs) and 10 received other interventions. Relapse was defined as very early (<6 months; 28%), early (6 to 24 months; 50%), or late (>24 months; 22%). At relapse, 27% presented with extramedullary disease (EMD). The median postrelapse overall survival (OS) by time to relapse was 4 months for the very early relapse group, 17 months for the early relapse group, and 72 months for the late relapse group (P = .002). Older age, relapse with EMD, <PR before alloHCT, <PR by day +100, and no maintenance were prognostic for inferior postrelapse OS on univariate analysis. On multivariate analysis adjusted for age and sex, very early relapse (hazard ratio [HR], 4.37; 95% confidence interval [CI], 1.42 to 13.5), relapse with EMD (HR, 5.20; 95% CI, 2.10 to 12.9), and DLI for relapse prevention (HR, .11; 95% CI, 2.10 to 12.9) were significant predictors for postrelapse survival. Despite their shared inherent high-risk status, patients with MM have significantly disparate post-HCT relapse courses, with some demonstrating long-term survival despite relapse.

A consensus grading schema for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) resulting from chimeric antigen receptor (CAR) T cell therapy was published in 2019. Although this consensus grading schema has been imperative in identifying and monitoring CRS and ICANS in our CAR T cell population, we observed patients exhibiting subtle neurotoxicity symptoms prior to a decrease in their immune effector cell-associated encephalopathy (ICE) score, which is one component of ICANS. Because we treat grade 1 ICANS at our institution, identification of early neurotoxicity symptoms is important. Additionally, we found changes in personality, occupational confusion, or inability to answer dichotomous questions were early signs of neurotoxicity. Therefore, we developed a 3-step command tool to supplement the ICE evaluation. We present 2 examples of patients who exhibited early neurotoxicity symptoms and led us to develop this tool and 1 in whom it was effective. We propose that CAR T cell patients are consistently followed by a clinical care provider who is familiar with the patient to recognize early changes in personality, behavior, and cognition. Additionally, we propose that the multistep command tool be used in conjunction with the ICE score to detect early symptoms of ICANS. Early intervention has the potential to prevent irreversible neurotoxicity.

Long-term therapy-related reproductive health side effects impact the quality of life of hematopoietic stem cell transplantation (HSCT) survivors. In this study, we evaluated the prevalence of gonadal dysfunction (GD) pre- and post-HSCT, analyzed factors associated with GD, and explored rates of fertility assessment (FA) and fertility preservation (FP) in a resource-limited setting. FA and outcomes of patients age ≤45 years undergoing HSCT between June 2000 and May 2018 were collected retrospectively. We included 213 patients with a median age of 26 years. Pre-HSCT FA was performed in 71.8%, with a GD rate of 17%. The rate of GD was not different between the sexes (females, 19.5% versus males, 16.1%; P = .616) and was only associated with increasing age. The rate of cryopreservation in the cohort was 3.3%. Almost one-half (47.7%) of post-HSCT patients completed FA and evidenced an increase in GD rate to 48.9%. Comparing pre-HSCT and post-HSCT GD rates, women had a significant increase (19.5% versus 81.4%; P < .001), whereas men did not (16.1% versus 20.4%; P = .76). These results were confirmed by a multiple imputation analysis accounting for missing data. Female sex, pre-HSCT cytotoxic therapy, myeloablative conditioning, and germ cell tumor (GCT) diagnosis were associated with post-HSCT GD. Reproductive health preservation can be positively impacted when FA and FP are prioritized at the initial diagnosis in HSCT candidates, particularly in women of older age and men with a diagnosis of GCT. The low FP success observed urges implementation of strategies that favor accessibility and improve quality of life of HSCT survivors in low- and middle-income countries.