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The sorafenib anti-relapse effect after alloHSCT is associated with heightened alloreactivity and accumulation of CD8+PD-1+ (CD279+) lymphocytes in marrow.
Lange, A, Jaskula, E, Lange, J, Dworacki, G, Nowak, D, Simiczyjew, A, Mordak-Domagala, M, Sedzimirska, M
PloS one. 2018;(1):e0190525
Abstract
We studied three FLT3 ITD acute myeloid leukemia (AML) patients who relapsed after allogeneic haematopoietic stem cell transplantation (alloHSCT) and received multikinase inhibitor (MKI) sorafenib as part of salvage therapy. MKI was given to block the effect of FLT3 ITD mutation which powers proliferation of blast cells. However, the known facts that sorafenib is more effective in patents post alloHSCT suggested that this MKI can augment the immune system surveillance on leukaemia. In the present study, we investigated in depth the effect of sorafenib on the alloreactivity seen post-transplant including that on leukaemia. The patients (i) responded to the treatment with cessation of blasts which lasted 1, 17 and 42+ months, (ii) developed skin lesions with CD3+ cell invasion of the epidermis, (iii) had marrow infiltrated with CD8+ lymphocytes which co-expressed PD-1 (programmed cell death protein 1 receptor, CD279) in higher proportions than those in the blood (163±32 x103 cells/μl vs 38±8 x103 cells/μl, p<0.001). The Lymphoprep fraction of marrow cells investigated for the expression of genes involved in lymphocyte activation showed in the patients with long lasting complete remission (CR) a similar pattern characterized by (i) a low expression of nitric oxide synthase 2 (NOS2) and colony stimulating factor 2 (CSF2) as well as that of angiopoietin-like 4 (ANGPTL4) (supporting the immune response and anti-angiogenic) genes, and (ii) higher expression of fibroblast growth factor 1 (FGF1) and collagen type IV alpha 3 chain (COL4A3) as well as toll like receptor 9 (TLR9) and interleukin-12 (IL-12) (pro-inflammatory expression profile) genes as compared with the normal individual. The positive effect in one patient hardly justified the presence of unwanted effects (progressive chronic graft-versus-host disease (cGvHD) and avascular necrosis of the femur), which were in contrast negligible in the other patient. The anti-leukemic and unwanted effects of sorafenib do not rely on each other.
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Echinocandin prophylaxis in patients undergoing haematopoietic cell transplantation and other treatments for haematological malignancies.
Epstein, DJ, Seo, SK, Brown, JM, Papanicolaou, GA
The Journal of antimicrobial chemotherapy. 2018;(suppl_1):i60-i72
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Abstract
Antifungal prophylaxis is the standard of care for patients undergoing intensive chemotherapy for haematological malignancy or haematopoietic cell transplantation (HCT). Prophylaxis with azoles reduces invasive fungal infections and may reduce mortality. However, breakthrough infections still occur, and the use of azoles is sometimes complicated by pharmacokinetic variability, drug interactions, adverse events and other issues. Echinocandins are highly active against Candida species, including some organisms resistant to azoles, and have some clinical activity against Aspergillus species as well. Although currently approved echinocandins require daily intravenous administration, the drugs have a favourable safety profile and more predictable pharmacokinetics than mould-active azoles. Clinical data support the efficacy and safety of echinocandins for antifungal prophylaxis in haematology and HCT patients, though data are less robust than for azoles. Notably, sparse evidence exists supporting the use of echinocandins as antifungal prophylaxis for patients with significant graft-versus-host disease (GvHD) after HCT. Two drugs that target (1,3)-β-d-glucan are in development, including an oral glucan synthase inhibitor and an echinocandin with unique pharmacokinetics permitting subcutaneous and weekly administration. Echinocandins are a reasonable alternative to azoles and other agents for antifungal prophylaxis in patients undergoing intensive chemotherapy for haematological malignancy or those receiving HCT, excluding those with significant GvHD.
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Deferasirox for the treatment of iron overload after allogeneic hematopoietic cell transplantation: multicenter phase I study (KSGCT1302).
Tachibana, T, Kanda, J, Machida, S, Saito, T, Tanaka, M, Najima, Y, Koyama, S, Miyazaki, T, Yamamoto, E, Takeuchi, M, et al
International journal of hematology. 2018;(5):578-585
Abstract
UNLABELLED The aim of this study was to assess the safety and optimal dose of deferasirox for the treatment of iron overload after allogeneic hematopoietic cell transplantation (HCT). The primary endpoint was the maximum tolerated dose of deferasirox that was determined by the intrapatient dose escalation methods. A total of 16 patients with post-HCT iron overload were enrolled in the study. After excluding one case of early relapse, 15 remained evaluable. Their median age was 42 years (range 22-68). Median time from HCT to deferasirox administration was 9 months (range 6-84). Deferasirox was started at a dose of 5 mg/kg, and the dose was increased to 7.5 and 10 mg/kg every 4 weeks unless there were no grade ≥ 2 of adverse events. Achievement rates of planned medication were 80% in 5 mg/kg (12 of 15), 73% in 7.5 mg/kg (11 of 15), and 60% in 10 mg/kg (9 of 15), respectively. The reasons for discontinuation of the drug were grade 2 of adverse events (n = 4), late relapse (n = 1), and self-cessation (n = 1). None of the patients developed grade ≥ 3 of adverse events or exacerbation of GVHD. Among 11 evaluable cases, mean value of ferritin decreased from 1560 ng/ml pre-treatment to 1285 ng/ml post-treatment. These data suggested that 10 mg/kg of deferasirox may be maximum tolerated dose when given after HCT. Our dose escalating method of deferasirox is useful to identify the optimal dosage of the drug in each patient. TRIAL REGISTRATION UMIN000011251.
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Hematopoietic Stem Cell Transplantation for Adult Philadelphia-Negative Acute Lymphoblastic Leukemia in the First Complete Remission in the Era of Minimal Residual Disease.
Bourlon, C, Lacayo-Leñero, D, Inclán-Alarcón, SI, Demichelis-Gómez, R
Current oncology reports. 2018;(4):36
Abstract
PURPOSE OF REVIEW The purpose of this review is to discuss the potential role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for Philadelphia-negative (Ph-) adult acute lymphoblastic leukemia (ALL) in first complete remission (CR1) in the era of minimal residual disease (MRD). RECENT FINDINGS Allo-HSCT continues to have a role in the therapy of a selected group of high-risk adult patients with ALL in CR1. Although the clinical significance of MRD has been studied less extensively in adults with ALL than in children, recent studies support its role as the strongest prognostic factor that can identify patients that are unlikely to be cured by standard chemotherapy and benefit from undergoing allo-HSCT. In addition, MRD status both pre- and post-HSCT has been found to correlate directly with the risk of relapse. Currently, the clinical challenge consists on applying MRD and molecular failure to integrate novel agents and immunotherapy to lower MRD before allo-HSCT and to modulate the graft versus leukemia (GVL) effect after transplant.
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Impact of body mass index at different transplantation stages on postoperative outcomes in patients with hematological malignancies: a meta-analysis.
Ren, G, Cai, W, Wang, L, Huang, J, Yi, S, Lu, L, Wang, J
Bone marrow transplantation. 2018;(6):708-721
Abstract
Although the association between body mass index (BMI) and overall survival (OS) has been reported in leukemia patients of different ages, whether BMI levels at different stages of hematopoietic stem cell transplantation (HSCT) have different effects on postoperative survival remains controversial. We searched four electronic databases from inception through July 2017 without any language restrictions and included studies on different types of hematological malignancies reporting both BMI time points and HSCT. Of the 1420 articles identified, 26 articles were eligible for inclusion in this meta-analysis. Three weight groups (obese, overweight and underweight) were individually compared with the normal group. Summary risk estimates for OS and event-free survival (EFS) were calculated with random- or fixed-effects models. For BMI at the pre-HSCT stage, a statistically significant positive association of increased risk of OS (RR: 1.17; 95% CI: 1.08-1.27) and EFS (RR: 1.29; 95% CI: 1-1.67) was identified in underweight individuals compared with those with normal weights. For BMI in the HSCT stage, a lower BMI was significantly associated with poorer OS (RR: 1.34; 95% CI: 1.01-1.78) and EFS (RR: 1.53; 95% CI: 1.09-2.06) compared with a normal BMI. Our results indicated that lower BMI at the pre-HSCT stage or during HSCT is associated with poorer survival.
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Optimization of nutrition during allogeneic hematologic stem cell transplantation.
Baumgartner, A, Hoskin, K, Schuetz, P
Current opinion in clinical nutrition and metabolic care. 2018;(3):152-158
Abstract
PURPOSE OF REVIEW Malnutrition before and during hematopoietic stem cell transplantation (HSCT) is an independent risk factor for mortality in patients undergoing hematopoietic stem cell transplantation. Yet, optimal use of nutritional support to improve outcomes remains controversial. Our aim was to do an up-to-date literature review regarding nutritional therapy in allogeneic HSCT, the neutropenic diet and the use of immunonutrients. RECENT FINDINGS Several observational studies find malnutrition to be associated with poor outcome, increased complications and lower overall survival. There are, however, few interventional trials proving the benefits of nutritional therapy in this population compared with no nutritional treatment. Regarding routes of treatment, studies suggested that parenteral nutrition is associated with higher risk for complications compared with enteral nutrition. Whether the use of specific formulas, such as immunonutrition, has a beneficial effect on clinical outcome is not established yet. Strict use of neutropenic diets did not show a reduction in infection risk and clinical outcome, and can no longer be recommended. SUMMARY Our updated search confirms that malnutrition is a strong negative predictor for outcome, yet optimal use of nutritional interventions to prevent or treat malnutrition remains ill-defined. There is need for larger randomized trials to better address these issues in the future.
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Type 2 Diabetes Mellitus, the Metabolic Syndrome, and Its Components in Adult Survivors of Acute Lymphoblastic Leukemia and Hematopoietic Stem Cell Transplantations.
Bielorai, B, Pinhas-Hamiel, O
Current diabetes reports. 2018;(6):32
Abstract
PURPOSE OF REVIEW A growing number of pediatric acute lymphoblastic leukemia (ALL) and hematopoietic stem cell transplantation (HSCT) survivors reach adulthood and face long-term health-related problems. We review risk factors and the prevalence of the metabolic syndrome (MetS), a cluster of obesity-related comorbidities, including abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, impaired glucose metabolism, and type 2 diabetes in ALL and HSCT survivors. RECENT FINDINGS Components of the MetS are already detected during the first year of ALL maintenance therapy and significantly worsen over time. The prevalence of MetS increases at a faster rate in this setting than in the general population. Factors found to be of the greatest potential risk to the development of the MetS are central obesity, increased BMI, irradiation therapy, older age, poor diet, and low level of physical activity. The early onset of MetS and its components among ALL and HSCT survivors calls for early and continuous screening to identify those at risk and to implement preventive measures.
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Quality of life during and following sequential treatment of previously untreated patients with multiple myeloma: findings of the Medical Research Council Myeloma IX randomised study.
Royle, KL, Gregory, WM, Cairns, DA, Bell, SE, Cook, G, Owen, RG, Drayson, MT, Davies, FE, Jackson, GH, Morgan, GJ, et al
British journal of haematology. 2018;(6):816-829
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Abstract
In the Medical Research Council (MRC) Myeloma IX trial (ISRCTN684564111) patients were randomised to sodium clodronate or zoledronic acid and induction treatment: cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) or cyclophosphamide, thalidomide and dexamethasone (CTD) followed by autologous stem cell transplant (ASCT) in the intensive pathway; attenuated CTD or melphalan and prednisolone (MP) in the non-intensive pathway. Subsequent randomisation allocated patients to either thalidomide or observation. The European Organisation for Research and Treatment of Cancer (EORTC) quality of life (QoL) questionnaires, QLQ-C30 and QLQ-MY24, were administered at baseline, 3, 6 and 12 months and annually thereafter, enabling the effect of sequential treatment on patient-reported health-related QoL (HR-QoL) to be investigated. The protocol specified four subscales of interest: Pain, Fatigue, Global Health Status/Quality of Life and Physical Functioning at 3, 6 and 12 months that were compared using linear models. The intensive pathway showed significant differences in favour of CTD for Fatigue at 3 months and Physical Functioning at 12 months. The non-intensive pathway and maintenance phase reported significant differences at 3 months; Pain (improved with attenuated CTD) and Global Health status/Quality of Life (improved with observation). The improved outcomes in MRC Myeloma IX were accompanied by some beneficial and few detrimental effects on HR-QoL.
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ECIL guidelines for the prevention, diagnosis and treatment of BK polyomavirus-associated haemorrhagic cystitis in haematopoietic stem cell transplant recipients.
Cesaro, S, Dalianis, T, Hanssen Rinaldo, C, Koskenvuo, M, Pegoraro, A, Einsele, H, Cordonnier, C, Hirsch, HH, ,
The Journal of antimicrobial chemotherapy. 2018;(1):12-21
Abstract
OBJECTIVES To define guidelines for BK polyomavirus (BKPyV)-associated haemorrhagic cystitis (BKPyV-HC) after paediatric and adult HSCT. METHODS Review of English literature and evidence-based recommendations by expert consensus. RESULTS BKPyV-HC occurs in 8%-25% of paediatric and 7%-54% of adult recipients undergoing allogeneic HSCT. Diagnosis requires the triad of cystitis, macro-haematuria and high urine BKPyV loads >7 log10 copies/mL, and exclusion of other relevant aetiologies. BKPyV viraemia is frequent and may serve as a more specific semiquantitative follow-up marker. No randomized controlled trials are available to inform antiviral prophylaxis or treatment. However, hyper-hydration and/or bladder irrigation showed limited prophylactic value. Fluoroquinolones are not effective for prophylaxis or treatment, but rather increase antibiotic resistance. Hyperbaric oxygen or fibrin glue is marginally effective based on small case series from correspondingly equipped centres. Although cidofovir has been reported to improve and/or reduce BKPyV viraemia or viruria, the current data do not support its regular use. CONCLUSIONS BKPyV-HC remains a disabling unmet clinical need in HSCT that requires novel approaches supported by proper clinical trials.
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Transplantation in patients with iron overload: is there a place for magnetic resonance imaging? : Transplantation in iron overload.
Mavrogeni, S, Kolovou, G, Bigalke, B, Rigopoulos, A, Noutsias, M, Adamopoulos, S
Heart failure reviews. 2018;(2):173-180
Abstract
In iron overload diseases (thalassemia, sickle cell, and myelodysplastic syndrome), iron is deposited in all internal organs, leading to functional abnormalities. Hematopoietic stem cell transplantation (HSCT) is the only treatment offering a potential cure in these diseases. Our aim was to describe the experience in the field and the role of magnetic resonance imaging in the evaluation of iron overload before and after HSCT. Magnetic resonance imaging (MRI), using T2*, is the most commonly used tool to diagnose myocardial-liver iron overload and guide tailored treatment. Currently, HSCT offers complete cure in thalassemia major, after overcoming the immunologic barrier, and should be considered for all patients who have a suitable donor. The overall thalassemia-free survival of low-risk, HLA-matched sibling stem cell transplantation patients is 85-90%, with a 95% overall survival. The problems of rejection and engraftment are improving with the use of adequate immunosuppression. However, a detailed iron assessment of both heart and liver is necessary for pre- and post-transplant evaluation. In iron overload diseases, heart and liver iron evaluation is indispensable not only for the patients' survival, but also for evaluation before and after HSCT.