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1.
Blood Adv ; 5(1): 262-273, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33570653

RESUMO

Type I and III leukocyte adhesion deficiencies (LADs) are primary immunodeficiency disorders resulting in early death due to infections and additional bleeding tendency in LAD-III. The curative treatment of LAD-I and LAD-III is allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this retrospective multicenter study, data were collected using the European Society for Blood and Marrow Transplantation registry; we analyzed data from 84 LAD patients from 33 centers, all receiving an allo-HSCT from 2007 to 2017. The 3-year overall survival estimate (95% confidence interval [CI]) was 83% (74-92) for the entire cohort: 84% (75-94) and 75% (50-100) for LAD-I and LAD-III, respectively. We observed cumulative incidences (95% CI) of graft failure (GF) at 3 years of 17% (9%-26%) and grade II to IV acute graft-versus-host disease (aGVHD) at 100 days of 24% (15%-34%). The estimate (95% CI) at 3 years for GF- and GVHD-II to IV-free survival as event-free survival (EFS) was 56% (46-69) for the entire cohort; 58% (46-72) and 56% (23-88) for LAD-I and LAD-III, respectively. Grade II to IV acute GVHD was a relevant risk factor for death (hazard ratio 3.6; 95% CI 1.4-9.1; P = .006). Patients' age at transplant ≥13 months, transplantation from a nonsibling donor, and any serological cytomegalovirus mismatch in donor-recipient pairs were significantly associated with severe acute GVHD and inferior EFS. The choice of busulfan- or treosulfan-based conditioning, type of GVHD prophylaxis, and serotherapy did not impact overall survival, EFS, or aGVHD. An intrinsic inflammatory component of LAD may contribute to inflammatory complications during allo-HSCT, thus providing the rationale for considering anti-inflammatory therapy pretreatment.

2.
Eur J Haematol ; 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33453130

RESUMO

OBJECTIVES: Secondary antibody deficiency (SAD), associated with severe, recurrent or persistent infections, is common in patients with haematological malignancies (HM), but unifying guidance on immunoglobulin replacement therapy (IgRT) in these patients is lacking. We aimed to develop consensus statements for the use of IgRT in patients with HM. METHODS: A Delphi exercise was employed to test the level of agreement on statements developed by a Task Force based on available data and their clinical experience. In Round 1, an Expert Panel, comprising specialist EU physicians caring for patients with HM, helped to refine the statements. In Round 2, experts rated their agreement with the statements. In Round 3, experts who had scored their agreement as ≤4 were invited to review their agreement based on the overall feedback. RESULTS: Three definitions and 20 statements were formulated and tested for consensus, covering measurement of IgG levels, initiation and discontinuation of IgRT, dosing, and the use of subcutaneous IgG. Consensus (agreement ≥70% on Likert-type scale) was reached for all three definitions and 18 statements. CONCLUSIONS: Recommendations have been developed with the aim of providing guidance for the use of IgRT to prevent severe, recurrent or persistent infections in patients with HM and SAD.

3.
J Gen Intern Med ; 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479925

RESUMO

BACKGROUND: Hypoglycemia is a common and serious adverse effect of diabetes treatment, especially for patients using insulin or insulin secretagogues. Guidelines recommend that these patients be assessed for interval hypoglycemic events at each clinical encounter and be provided anticipatory guidance for hypoglycemia prevention. OBJECTIVE: To determine the frequency and content of hypoglycemia communication in primary care visits. DESIGN: Qualitative study PARTICIPANTS: We examined 83 primary care visits from one urban health practice representing 8 clinicians and 33 patients using insulin or insulin secretagogues. APPROACH: Using a directed content analysis approach, we analyzed audio-recorded primary care visits collected as part of the Achieving Blood Pressure Control Together study, a randomized trial of behavioral interventions for hypertension. The coding framework included communication about interval hypoglycemia, defined as discussion of hypoglycemic events or symptoms; the components of hypoglycemia anticipatory guidance in diabetes guidelines; and hypoglycemia unawareness. Hypoglycemia documentation in visit notes was compared to visit transcripts. KEY RESULTS: Communication about interval hypoglycemia occurred in 24% of visits, and hypoglycemic events were reported in 16%. Despite patients voicing fear of hypoglycemia, clinicians rarely assessed hypoglycemia frequency, severity, or its impact on quality of life. Hypoglycemia anticipatory guidance was provided in 21% of visits which focused on diet and behavior change; clinicians rarely counseled on hypoglycemia treatment or avoidance of driving. Limited discussions of hypoglycemia unawareness occurred in 8% of visits. Documentation in visit notes had low sensitivity but high specificity for ascertaining interval hypoglycemia communication or hypoglycemic events, compared to visit transcripts. CONCLUSIONS: In this high hypoglycemia risk population, communication about interval hypoglycemia and counseling for hypoglycemia prevention occurred in a minority of visits. There is a need to support clinicians to more regularly assess their patients' hypoglycemia burden and enhance counseling practices in order to optimize hypoglycemia prevention in primary care.

4.
Radiother Oncol ; 155: 113-119, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33137397

RESUMO

BACKGROUND AND PURPOSE: To reduce relapse risk, Total Body Irradiation (TBI) is part of conditioning regimens for hematopoietic stem cell transplantation (HSCT) in pediatric acute leukemia. The study purpose was to evaluate clinical practices regarding TBI, such as fractionation, organ shielding and delivery techniques, among SIOPE affiliated radiotherapy centers. METHODS: An electronic survey was sent out to 233 SIOPE affiliated centers, containing 57 questions about clinical practice of TBI. Surveys could be answered anonymously. RESULTS: From over 25 countries, 82 responses were collected. For TBI-performing centers, 40/48 irradiated ≤10 pediatric patients annually (range: 1-2 to >25). Most indications concerned acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Four different fractionation schedules were used, of which 12 Gy in 6 fractions was applied in 91% for ALL and 86% for AML. Dose reduction to the lungs, mostly to a mean dose of 8-10 Gy, was applied by 28/33 centers for ALL and 19/21 centers for AML, in contrast to much less applied dose reduction to the kidneys (7/33 ALL and 7/21 AML), thyroid (2/33 ALL and 2/21 AML), liver (4/33 ALL and 3/21 AML) and lenses (4/33 ALL and 4/21 AML). Conventional TBI techniques were used by 24/29 responding centers, while 5/29 used advanced optimized planning techniques. CONCLUSION: Across SIOPE, there is a high level of uniformity in fractionation and use of lung shielding. Practices vary regarding other organs-at-risk shielding and implementation of advanced techniques. A SIOPE radiotherapy working group will be established to define international guidelines for pediatric TBI.

5.
Blood ; 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33094319

RESUMO

Emerging immunotherapies such as chimeric antigen receptor T cells have advanced the treatment of acute lymphoblastic leukemia. In contrast, long-term control of acute myeloid leukemia (AML) cannot be achieved by single lineage-specific targeting while sparing benign hematopoiesis. In addition, heterogeneity of AML warrants combinatorial targeting and several suitable immunotargets (HAVCR2/CD33 or HAVCR2/CLEC12A) were identified in adult AML. However, clinical and biologic characteristics differ between children and the elderly. Here, we analyzed 36 bone marrow (BM) samples of pediatric AML patients and 13 age-matched healthy donors using whole RNA-sequencing of sorted CD45dim and CD34+CD38-CD45dim BM populations and flow cytometry for surface expression of putative target antigens. Pediatric AML clusters apart from healthy myeloid BM precursors in principle component analysis. Immunotargets known from adult AML such as IL3RA were not overexpressed in pediatric AML compared to healthy precursors by RNA-sequencing. CD33 and CLEC12A were the most upregulated immunotargets on RNA level and showed the highest surface expression on AML detected by flow cytometry. KMT2A mutated infant AML cluster separately by RNA-sequencing, overexpress FLT3 and hence CD33/FLT3 co-targeting is an additional specific option for this subgroup. CLEC12A and CD33/CLEC12Adouble-positive expression was absent in CD34+CD38-CD45RA-CD90+ hematopoietic stem cells (HSC) and both are restricted to healthy hematopoietic tissue, while CD33 and FLT3 is expressed on HSC. In summary, we show that expression of immunotargets in pediatric AML differs from known expression profiles in adult AML. We identify CLEC12A/CD33 as preferential generic combinatorial immunotargets in pediatric AML and CD33/FLT3 as immunotargets specific for KMT2A mutated infant AML.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33118209

RESUMO

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) can cure chronic granulomatous disease (CGD), but it remains debated whether all conventionally treated CGD patients benefit from HSCT. METHODS: We retrospectively analyzed 104 conventionally treated CGD patients, of whom 50 patients underwent HSCT. RESULTS: On conventional treatment, seven patients (13%) died after a median time of 16.2 years (interquartile range [IQR] 7.0-18.0). Survival without severe complications was 10 ± 3% (mean ± SD) at the age of 20 years; 85% of patients developed at least one infection, 76% one non-infectious inflammation. After HSCT, 44 patients (88%) were alive at a median follow-up of 2.3 years (IQR 0.8-4.9): Six patients (12%) died from infections. Survival after HSCT was significantly better for patients transplanted ≤8 years (96 ± 4%) or for patients without active complications at HSCT (100%). Eight patients suffered from graft failure (16%); six (12%) developed acute graft-vs-host disease requiring systemic treatment. Conventionally treated patients developed events that required medical attention at a median frequency of 1.7 (IQR 0.8-3.2) events per year vs 0 (IQR 0.0-0.5) in patients beyond the first year post-HSCT. While most conventionally treated CGD patients failed to thrive, catch-up growth after HSCT in surviving patients reached the individual percentiles at the age of diagnosis of CGD. CONCLUSION: Chronic granulomatous disease patients undergoing HSCT until 8 years of age show excellent survival, but young children need more intense conditioning to avoid graft rejection. Risks and benefits of HSCT for adolescents and adults must still be weighed carefully.

7.
Clin Cancer Res ; 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33082212

RESUMO

PURPOSE: Nijmegen breakage syndrome (NBS) is a DNA repair disorder with a high predisposition to hematologic malignancies. EXPERIMENTAL DESIGN: We describe the natural history of NBS, including cancer incidence, risk of death, and the potential effectiveness of hematopoietic stem cell transplantation (HSCT) in preventing both pathologies: malignancy and immunodeficiency. RESULTS: Among 241 patients with NBS enrolled in the study from 11 countries, 151 (63.0%) patients were diagnosed with cancer. Incidence rates for primary and secondary cancer, tumor characteristics, and risk factors affecting overall survival (OS) were estimated. The cumulative cancer incidence was 40.21% ± 3.5% and 77.78% ± 3.4% at 10 years and 20 years of follow-up, respectively. Most of the tumors n = 95 (62.9%) were non-Hodgkin lymphomas. Overall, 20 (13.2%) secondary malignancies occurred at a median age of 18 (interquartile range, 13.7-21.5) years. The probability of 20-year overall survival (OS) for the whole cohort was 44.6% ± 4.5%. Patients who developed cancer had a shorter 20-year OS than those without malignancy (29.6% vs. 86.2%; P < 10-5). A total of 49 patients with NBS underwent HSCT, including 14 patients transplanted before malignancy. Patients with NBS with diagnosed cancer who received HSCT had higher 20-year OS than those who did not (42.7% vs. 30.3%; P = 0.038, respectively). In the group of patients who underwent preemptive transplantation, only 1 patient developed cancer, which is 6.7 times lower as compared with nontransplanted patients [incidence rate ratio 0.149 (95% confidence interval, 0.138-0.162); P < 0.0001]. CONCLUSIONS: There is a beneficial effect of HSCT on the long-term survival of patients with NBS transplanted in their first complete remission of cancer.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33022377

RESUMO

BACKGROUND: Patients with primary immunodeficiencies caused by severe defects in T-cell immunity are at risk of acquiring life-threatening viral or opportunistic infections. Cellular therapies are necessary to establish normal T-cell function and to allow for long-term survival. This is most commonly achieved by hematopoietic stem cell transplantation (HSCT) but the outcome of this procedure is impaired if active infections are present at the time of HSCT. Donor lymphocyte infusions (DLI) are a well-established therapeutic strategy following HSCT to treat viral infections, to improve donor cell engraftment or to achieve graft versus leukemia activity in malignant disease. OBJECTIVE: The objective of our study is to demonstrate the feasibility and efficacy of DLIs as first cellular therapy in the treatment of patients with severe T-cell deficiencies. STUDY DESIGN: We performed a retrospective analysis of data originating from a cohort of six patients with primary T-cell deficiencies who were treated in four different centers and who received transfusions of unselected mature donor lymphocytes prior and not directly related to allogeneic HSCT. DLIs obtained from the peripheral blood of HLA-identical (10/10) family donors were transfused without prior conditioning to treat or to prevent life-threatening infections. RESULTS: All patients are alive with a follow-up of 0.5 to 16.5 years after the initial T-cell administration. Additional cellular therapies were administered in 5/6 patients at 0.8 to 15 months after the first DLI. Mild cutaneous graft-versus-host disease (GvHD, stage ≤2) was observed in 3/6 patients and resolved spontaneously. CONCLUSION: We provide evidence that unselected HLA-identical DLIs can effectively prevent or contribute to overcome infections with a limited risk for GvHD in T-cell deficient patients. The T-cell system established by this readily available source can provide T-cell function for years and can serve as a bridge to additional cellular therapies or -in specific conditions- as definite treatment.

9.
Br J Haematol ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33022753

RESUMO

Few effective therapies exist for acute myeloid leukaemia (AML), in part due to the molecular heterogeneity of this disease. We sought to identify genes crucial to deregulated AML signal transduction pathways which, if inhibited, could effectively eradicate leukaemia stem cells. Due to difficulties in screening primary cells, most previous studies have performed next-generation sequencing (NGS) library knockdown screens in cell lines. Using carefully considered methods including evaluation at multiple timepoints to ensure equitable gene knockdown, we employed a large NGS short hairpin RNA (shRNA) knockdown screen of nearly 5 000 genes in primary AML cells from six patients to identify genes that are crucial for leukaemic survival. Across various levels of stringency, genome-wide bioinformatic analysis identified a gene in the NOX family, NOX1, to have the most consistent knockdown effectiveness in primary cells (P = 5∙39 × 10-5 , Bonferroni-adjusted), impacting leukaemia cell survival as the top-ranked gene for two of the six AML patients and also showing high effectiveness in three of the other four patients. Further investigation of this pathway highlighted NOX2 as the member of the NOX family with clear knockdown efficacy. We conclude that genes in the NOX family are enticing candidates for therapeutic development in AML.

10.
J Immunother Cancer ; 8(2)2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32938628

RESUMO

BACKGROUND: Relapsed/refractory B-precursor acute lymphoblastic leukemia (BCP-ALL) remains a major therapeutic challenge in pediatric hematology. Chimeric antigen receptor (CAR) T cells targeting CD19 have shown remarkable initial response rates in BCP-ALL patients, while long-term leukemia control rate is only about 50%. So far, main mechanisms of BCP-ALL relapse after CD19-CAR T-cell therapy have been either insufficient CAR T-cell persistence in vivo or loss of surface CD19. CASE REPORT: Here, we report an exceptional presentation of BCP-ALL relapse in the eye during the systemic control through CAR T-cell therapy. We report a case of fatal intraocular relapse in a pediatric patient with pro-B-ALL after initial response to CD19-CAR T-cell therapy. One month after CD19-CAR T-cell therapy, remission was documented by bone marrow aspirate analysis with absence of CD19+ cells and CD19-CAR T cells could be detected in both peripheral blood and bone marrow. At the same time, however, the patient presented with progressive visual disturbance and CD19+ cells were found within the anterior chamber of the eye. Despite local and systemic therapy, ocular relapse led to BCP-ALL dissemination and systemic relapse within weeks. The eye represents a rare site for local manifestation of BCP-ALL, but isolated intraocular relapse is a clinically unreckoned presentation of BCP-ALL in the era of CD19-CAR T cells. CONCLUSION: During systemic control of BCP-ALL through CD19-CAR T cells, relapse can emerge in the eye as an immune-privileged organ. Ocular symptoms after CD19-CAR T-cell therapy should guide the clinician to elucidate the etiology in a timely fashion in order to adjust leukemia treatment strategy. Both, local immune escape as well as insufficient CAR T-cell persistence may have contributed to relapse in the reported patient. Mechanisms of relapse in an immune desert under CAR T-cell therapy require future clinical and experimental attention. In particular, ocular symptoms after CAR T-cell therapy should be considered a potentially early sign of leukemia relapse.

11.
Blood ; 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32911532

RESUMO

BCL6 is a transcription repressor and proto-oncogene that plays a crucial role in the innate and adaptive immune system and lymphoid neoplasms. However, its role in myeloid malignancies remains unclear. Here, we explored the role of BCL6 in acute myeloid leukemia (AML). BCL6 was expressed at variable and often high levels in AML cell lines and primary AML samples. AMLs with higher levels of BCL6 were generally sensitive to treatment with BCL6 inhibitors with the exception of those with monocytic differentiation. Gene expression profiling of AML cells treated with BCL6 inhibitor revealed induction of BCL6 repressed target genes and transcriptional programs linked to DNA damage checkpoints and downregulation of stem cell genes. Ex vivo treatment of primary AML cells with BCL6 inhibitor induced apoptosis and decreased colony forming capacity which correlated with the levels of BCL6 expression. Importantly, inhibition or knockdown of BCL6 in primary AML cells resulted in significant reduction of leukemia initiating capacity in mice, suggesting ablation of leukemia repopulating cell functionality. In contrast, BCL6 knockout or inhibition did not suppress the function of normal HSCs. Treatment with cytarabine (AraC) further induced BCL6 expression, and the levels of BCL6 induction were correlated with resistance to AraC. Treatment of AML patient derived xenografts (PDX) with BCL6 inhibitor plus Ara-C suggested enhanced anti-leukemia activity by this combination. Hence pharmacological inhibition of BCL6 might provide a novel therapeutic strategy for ablation of leukemia-repopulating cells and increased responsiveness to chemotherapy.

13.
J Allergy Clin Immunol Pract ; 8(9): 3102-3111, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32603902

RESUMO

BACKGROUND: Complete signal transducer and activator of transcription 1 (STAT1) deficiency causes a rare primary immunodeficiency that is characterized by defective IFN-dependent gene expression leading to life-threatening viral and mycobacterial infections early in life. OBJECTIVE: To characterize a novel STAT1 loss-of-function variant leading to pathological infection susceptibility and hyperinflammation. METHODS: Clinical, immunologic, and genetic characterization of a patient with severe infections and hemophagocytic lymphohistiocytosis-like hyperinflammation was investigated. RESULTS: We reported a child of consanguineous parents who presented with multiple severe viral infections that ultimately triggered hemophagocytic lymphohistiocytosis and liver failure. Despite intensified therapy with antivirals and cytomegalovirus-specific donor cells, the child died after hematopoietic stem cell transplantation because of cytomegalovirus reactivation with acute respiratory distress syndrome. Exome sequencing revealed a homozygous STAT1 variant (p.Val339ProfsTer18), leading to loss of STAT1 protein expression. Upon type I and type II IFN stimulation, immune and nonimmune cells showed defective upregulation of IFN-stimulated genes and increased susceptibility to viral infection in vitro. Increased viral infection rates were paralleled by hyperinflammatory ex vivo cytokine responses with increased production of TNF, IL-6, and IL-18. CONCLUSIONS: Complete STAT1 deficiency is a devastating disorder characterized by severe viral infections and ensuing hyperinflammatory responses. Early diagnosis can be made by exome sequencing and variant validation by functional testing of STAT1-dependent programmed cell death 1 ligand 1 surface expression on monocytes. Furthermore, high awareness for hyperinflammatory complications and potential targeted treatment strategies such as IL-18 binding protein could be considered. Hematopoietic stem cell transplantation is the only definitive treatment strategy but remains challenging.

14.
Blood ; 136(10): 1201-1211, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32614953

RESUMO

Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can cure the disease, but the indication to transplant remains controversial. We performed a retrospective multicenter study of 712 patients with CGD who underwent allo-HCT transplantation from March 1993 through December 2018. We studied 635 children (aged <18 years) and 77 adults. Median follow-up was 45 months. Median age at transplantation was 7 years (range, 0.1-48.6). Kaplan-Meier estimates of overall survival (OS) and event-free survival (EFS) at 3 years were 85.7% and 75.8%, respectively. In multivariate analysis, older age was associated with reduced survival and increased chronic graft-versus-host disease. Nevertheless, OS and EFS at 3 years for patients ≥18 years were 76% and 69%, respectively. Use of 1-antigen-mismatched donors was associated with reduced OS and EFS . No significant difference was found in OS, but a significantly reduced EFS was noted in the small group of patients who received a transplant from a donor with a >1 antigen mismatch. Choice of conditioning regimen did not influence OS or EFS. In summary, we report an excellent outcome after allo-HCT in CGD, with low incidence of graft failure and mortality in all ages. Older patients and recipients of 1-antigen-mismatched grafts had a less favorable outcome. Transplantation should be strongly considered at a younger age and particularly in the presence of a well-matched donor.

15.
Pediatr Blood Cancer ; 67(9): e28523, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32618429

RESUMO

BACKGROUND: Reduced toxicity conditioning for hematopoietic stem cell transplantation of patients with hemophagocyticlymphohistiocytosis (HLH) results in favorable survival, however at the expense of relevant rates of mixed chimerism. Factors predisposing to mixed chimerism remain to be determined. PROCEDURE: Patients with primary HLH transplanted 2009-2016 after treosulfan- or melphalan-based conditioning regimens were analyzed in a retrospective multicenter study for survival, engraftment, chimerism, and adverse events. Mixed chimerism was considered substantial if < 25% donor chimerism occurred and/or if secondary cell therapy was administered. Donor type, graft source, type of alkylating agent, type of serotherapy, and remission status were analyzed as potential risk factors in a multivariable logistic regression model. RESULTS: Among 60 patients, engraftment was achieved in 95%, and the five-year estimated overall survival rate was 75%. Prevalence of any recipient chimerism was 48%. Substantial recipient chimerism was recorded in 32% of patients. Secondary post-HSCT cell therapy was administered in 30% of patients. A human leukocyte antigen (HLA)-mismatched donor (< 10/10) was the only significant risk factor for the occurrence of substantial recipient chimerism (P = 0.01; odds ratio, 5.8; CI 95%, 1.5-26.3). CONCLUSION: The use of an HLA-matched donor is the most important factor to avoid substantial recipient chimerism following treosulfan -or melphalan-based conditioning in primary HLH.

16.
Blood Adv ; 4(9): 1998-2010, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32384542

RESUMO

Reduced-intensity/reduced-toxicity conditioning and allogeneic T-cell replete hematopoietic stem cell transplantation are curative in patients with hemophagocytic lymphohistiocytosis (HLH). Unstable donor chimerism (DC) and relapses are clinical challenges . We examined the effect of a reduced-intensity conditioning regimen based on targeted busulfan to enhance myeloid DC in HLH. The European Society for Bone and Marrow Transplantation-approved reduced-intensity conditioning protocol comprised targeted submyeloablative IV busulfan, IV fludarabine, and serotherapy comprising IV alemtuzumab (0.5-0.8 mg/kg) for unrelated-donor and IV rabbit anti-T-cell globulin for related-donor transplants. We assessed toxicity, engraftment, graft-versus-host disease (GHVD), DC in blood cell subtypes, and overall survival/event-free survival. Twenty-five patients from 7 centers were treated (median age, 0.68 year). The median total dose and cumulative area under the curve of busulfan was 13.1 mg/kg (6.4-26.4) and 63.1 mg/L × h (48-77), respectively. Bone marrow, peripheral blood stem cell, or cord blood transplants from HLA-matched related (n = 7) or unrelated (n = 18) donors were administered. Donor cells engrafted in all patients (median: neutrophils d+20/platelets d+28). At last follow-up (median, 36 months; range, 8-111 months), the median DC of CD15+ neutrophils, CD3+ T cells, and CD16+56+ natural killer cells was 99.5% (10-100), 97% (30-100), and 97.5% (30-100), respectively. Eight patients (32%) developed sinusoidal obstruction syndrome, resolving after defibrotide treatment. The 3-year overall survival and event-free survival rates were both 100%. None of the patients developed acute grade III to IV GHVD. Limited chronic GVHD was encountered in 4%. This regimen achieves excellent results with stable DC in patients with HLH.

18.
Blood Adv ; 4(8): 1760-1769, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32343795

RESUMO

Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia associated with congenital abnormalities and cancer predisposition. Allogeneic hematopoietic stem cell transplantation (HSCT) can correct the hematological phenotype and is indicated in transfusion-dependent patients. In 70 children reported to the German DBA and French HSCT registries, HSCT was performed from 1985 to 2017. Median age at HSCT was 5.5 years (range, 0.9-17.3 years). Two-thirds of patients (64%) were transplanted from a matched sibling donor (MSD), and most procedures were performed after the year 1999 (73%). Primary engraftment was achieved in all patients. One patient developed secondary graft failure. Cumulative incidence of acute graft-versus-host disease (GVHD) was 24% for °II-IV (95% confidence interval [CI], 16% to 37%) and 7% for °III-IV (95% CI, 3% to 17%); cumulative incidence of chronic GVHD was 11% (95% CI, 5% to 22%). The probability of chronic GVHD-free survival (cGFS) was 87% (95% CI, 79% to 95%) and significantly improved over time (<2000: 68% [95% CI, 47% to 89%] vs ≥2000: 94% [95% CI, 87% to 100%], P < .01). cGFS was comparable following HSCT from a MSD and an unrelated donor (UD). Of note, no severe chronic GVHD or deaths were reported following MSD-HSCT after 1999. The difference of cGFS in children transplanted <10 years of age compared with older patients did not reach statistical significance (<10 years: 90% [95% CI, 81% to 99%] vs 10-18 years 78% [95% CI, 58% to 98%]). In summary, these data indicate that HSCT is efficient and safe in young DBA patients and should be considered if a MSD or matched UD is available. HSCT for transfusion dependency only must be critically discussed in older patients.

19.
Int J Cancer ; 147(8): 2159-2175, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32239677

RESUMO

Reports on pediatric low-grade diffuse glioma WHO-grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2-entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub-entities proved unfavorable for survival. Within the prospectively registered, population-based German/Swiss SIOP-LGG 2004 cohort 100 patients (age 0.8-17.8 years, 4% neurofibromatosis [NF1]) were diagnosed with a DG2. Following biopsy (41%) or variable extent of resection (59%), 65 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemotherapy (n = 18) or radiotherapy (n = 17). Multiple lines of salvage treatment were necessary for 19/35 patients. Five years event-free survival dropped to 0.44, while 5 years overall survival was 0.90 (median observation time 8.3 years). Extensive genetic profiling of 65/100 DG2 identified Histone3-K27M-mutation in 4, IDH1-mutation in 11, BRAF-V600-mutation in 12, KIAA1549-BRAF-fusions in 6 patients, while the remaining 32 tumor tissues did not show alterations of these genes. Progression to malignant glioma occurred in 12 cases of all genetically defined subgroups within a range of 0.5 to 10.8 years, except for tumors carrying KIAA1549-BRAF-fusions. Histone3-K27M-mutant tumors proved uniformly fatal within 0.6 to 2.4 years. The current LGG treatment strategy seems appropriate for all DG2-entities, with the exemption of Histone3-K27M-mutant tumors that require a HGG-related treatment strategy. Our data confirm the importance to genetically define pediatric low-grade diffuse gliomas for proper treatment decisions and risk assessment.

20.
Wien Klin Wochenschr ; 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32246210

RESUMO

BACKGROUND: The psychometric properties of an instrument, the Activity Scale for Kids-performance (ASKp), were assessed which was proposed to capture physical functioning after allogeneic hematopoietic stem cell transplantation (HSCT). Additionally, this multicenter observational prospective study investigated the influence of clinical correlates focusing on chronic graft-versus-host disease (cGVHD). METHODS: Patient-reported ASKp, clinician-reported Karnofsky/Lansky status (KPS/PSS), patient characteristics and cGVHD details were assessed of 55 patients with a median age of 12 years at baseline after day +100 post-HSCT and every 3 months during the next 18 months. The psychometric properties were evaluated and ASKp and KPS/PSS status was compared using ANOVAS and multiple regression models. RESULTS: The German version of the ASKp showed good psychometric properties except for ceiling effects. Discrimination ability of the ASKp was good regarding the need for devices but failed to predict cGVHD patients. Both the ASKp and the KPS/PSS were associated with patients after adoptive cell therapy being in need for devices, suffering from overlap cGVHD and from steroid side effects but not with patients' age and gender. In contrast to the KPS/PSS the ASKp only showed significant differences after merging moderate and severe cGHVD patients when comparing them to No-cGVHD (F = 4.050; p = 0.049), being outperformed by the KPS/PSS (F = 20.082; p < 0.001). CONCLUSION: The ASKp showed no clear advantages compared to KPS/PSS even though economical and patients' effort was higher. Further application range may be limited through ceiling effects. Both should be taken into consideration. Therefore, the results may not support the usage of ASKp after HSCT and rather suggest KPS/PSS, both patient and clinician reported.

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