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2.
Pediatr Blood Cancer ; : e28865, 2020 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-33369023

RESUMO

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome (MDS)/myeloproliferative disorder most commonly seen in the elderly. We describe an adolescent with monosomy 7 CMML presenting as central diabetes insipidus (DI), who was treated with venetoclax and decitabine as a bridge to hematopoietic stem cell transplantation (HSCT). Central DI is a rare manifestation of monosomy 7-associated MDS including CMML, itself a rare manifestation of GATA2 deficiency, particularly in children. Venetoclax/decitabine was effective for treatment of CMML as a bridge to HSCT.

3.
Semin Hematol ; 57(3): 115-121, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33256900

RESUMO

The introduction of chimeric antigen receptor (CAR) T-cell therapy in acute lymphoblastic leukemia (ALL) has dramatically altered the landscape of treatment options available to children and adults with ALL. With complete remission induction rates exceeding 70% in most trials and FDA approval of one CD19 CAR T-cell construct in ALL, CAR T-cell therapy has become a mainstay in the ALL treatment algorithm for those with relapsed/refractory disease. Despite the high remission induction rate, with growing experience using CAR T-cell therapy in ALL, a host of barriers to maintaining long-term durable remissions have been identified. Specifically, relapse after, resistance to, or loss of long-term CAR T-cell persistence may all hinder CAR T-cell efficacy. In this review, we provide an overview of the current limitations which inform the design of the next generation of CAR T-cells and discuss advances in CAR T-cell engineering aimed to improve upon outcomes with CAR T-cell-based therapy in ALL.

4.
J Immunother Cancer ; 8(2)2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33246985

RESUMO

Immunotherapeutic strategies targeting B-cell acute lymphoblastic leukemia (B-ALL) effectively induce remission; however, disease recurrence remains a challenge. Due to the potential for antigen loss, antigen diminution, lineage switch or development of a secondary or treatment-related malignancy, the phenotype and manifestation of subsequent leukemia may be elusive. We report on two patients with multiply relapsed/refractory B-ALL who, following chimeric antigen receptor T-cell therapy, developed myeloid malignancies. In the first case, a myeloid sarcoma developed in a patient with a history of myelodysplastic syndrome. In the second case, two distinct events occurred. The first event represented a donor-derived myelodysplastic syndrome with monosomy 7 in a patient with a prior hematopoietic stem cell transplantation. This patient went on to present with lineage switch of her original B-ALL to ambiguous lineage T/myeloid acute leukemia. With the rapidly evolving field of novel immunotherapeutic strategies, evaluation of relapse and/or subsequent neoplasms is becoming increasingly more complex. By virtue of these uniquely complex cases, we provide a framework for the evaluation of relapse or evolution of a subsequent malignancy following antigen-targeted immunotherapy.

5.
Nat Med ; 26(12): 1813-1814, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33230341
6.
Blood ; 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33206937

RESUMO

A disease risk index (DRI) that was developed for adults with hematologic malignancy undergoing hematopoietic cell transplant is also being used to stratify children and adolescents by disease risk. Therefore, in this study, we analyzed 2569 patients aged <18 years with acute myeloid (AML; n=1224) or lymphoblastic (ALL; n=1345) leukemia undergoing hematopoietic cell transplant to develop and validate a DRI that may be used to stratify those with AML and ALL by their disease risk. Training and validation subsets for each disease were generated randomly with 1:1 assignment to the subsets and separate prognostic models were derived for each disease. For AML, four risk groups were identified based on age, cytogenetic risk, and disease status including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2, 3, 5), high (7, 8), and very high (>8) risk groups were 78%, 53%, 40%, and 25%, respectively, p<0.0001. For ALL, three risk groups were identified based on age and disease status including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2-4), and high (≥5) risk groups were 68%, 51%, and 33%, respectively, p<0.0001. We confirmed the risk groups can be applied for overall survival with 5-year survival ranged from 80% to 33% and 73% to 42% for AML and ALL, respectively (p<0.0001). This validated pediatric DRI that includes age and residual disease status can be used to facilitate prognostication and stratification of children with AML and ALL for allogeneic transplantation.

7.
Cancer Cell ; 38(4): 429-432, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33049203

RESUMO

As we continue to learn about the unique biology of pediatric and childhood cancers and as new therapies are being developed, we asked some experts to highlight the most notable advances in our understanding of these diseases and in the development of treatments in the past decade, and to point out current challenges that still need to be addressed.

8.
3 Biotech ; 10(10): 415, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32953378

RESUMO

The gas chromatography of hexane extracts from ascocarps of Tuber maculatum (mostly the first report), T. aestivum/unicantum, T. borchii, T. melanosporum and Tirmania nivea dominantly showed palmitic, stearic, oleic and linoleic acids followed by traces of polyunsaturated fatty acids. The fatty acid content varied from ca. 8-61 mg g- 1, dry-weight-basis with species with highest for T. maculatum. Polyunsaturated fatty acids contributions varied from ca. 42-59%. The dominant fatty acid varied with the species. A comparison with existing reports on same species cultivated in different regions showed differences in contributions by saturated, monounsaturated and polyunsaturated fatty acids as well as dominant fatty acids detected. Lesser explored species such as T. borchii, T. maculatum call for further research. This is a preliminary study that indicates fatty acid composition as a potential tool for distinction like aroma between truffle species and geographies of cultivation. This forms the basis for further studies in different species and regions.

9.
J Immunother Cancer ; 8(2)2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32883871

RESUMO

BACKGROUND: Chimeric antigen receptor (CAR) T-cell-associated cytokine release syndrome (CRS) may present with tachycardia, hemodynamic instability and reduced cardiac function. Pediatric CAR studies examining cardiac toxicity are limited. METHODS: We report on cardiac toxicity observed in children and young adults with hematologic malignancies enrolled in a CD19-28ζ CAR T-cell phase I trial (NCT01593696). All patients had a formal baseline echocardiogram. Real-time studies included echocardiograms on intensive care unit (ICU) transfer, and serial troponin and pro-B-type natriuretic peptide (pro-BNP) in the select patients. RESULTS: From July 2012 to March 2016, 52 patients, with a median age of 13.4 years (range 4.2-30.3) were treated. CRS developed in 37/52 (71%), which was grade 3-4 CRS in nine patients (17%). The median prior anthracycline exposure was 205 mg/m2 (range 70-620 mg/m2) in doxorubicin equivalents. The median baseline left ventricle ejection fraction (LVEF) and baseline LV global longitudinal strain (GLS) were 60% (range 50%-70%) and 16.8% (range 14.1%-23.5%, n=37) respectively. The majority, 78% (29/37), of patients had a reduced GLS <19% at baseline, and 6% (3/52) of patients had baseline LVEF <53%. ICU transfers occurred in 21 patients, with nine requiring vasoactive hemodynamic support and three necessitating >1 vasopressor. Six (12%) patients developed cardiac dysfunction (defined by >10% absolute decrease in LVEF or new-onset grade 2 or higher LV dysfunction, per CTCAE v4), among whom 4 had grade 3-4 CRS. Troponin elevations were seen in 4 of 13 patients, all of whom had low LVEF. Pro-BNP was elevated from baseline in 6/7 patients at the onset of CRS, with higher levels correlating with more severe CRS. Cardiac dysfunction fully resolved in all but two patients by day 28 post-CAR. CONCLUSION: Cardiac toxicity related to CD19-28ζ CAR T-cell-associated CRS was generally reversible by day 28 postinfusion. Implementation of more frequent monitoring with formal echocardiograms incorporating systemic analysis of changes in GLS, and cardiac biomarkers (troponin and proBNP) may help to earlier identify those patients at highest risk of severe cardiac systolic dysfunction, facilitating earlier interventions for CRS to potentially mitigate acute cardiac toxicity.

10.
J Clin Invest ; 130(10): 5425-5443, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32925169

RESUMO

Late-onset inflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) occur after chimeric antigen receptor T cell (CAR T cell) infusion and represent a therapeutic challenge. Given the established link between perforin deficiency and primary HLH, we investigated the role of perforin in anti-CD19 CAR T cell efficacy and HLH-like toxicities in a syngeneic murine model. Perforin contributed to both CD8+ and CD4+ CAR T cell cytotoxicity but was not required for in vitro or in vivo leukemia clearance. Upon CAR-mediated in vitro activation, perforin-deficient CAR T cells produced higher amounts of proinflammatory cytokines compared with WT CAR T cells. Following in vivo clearance of leukemia, perforin-deficient CAR T cells reexpanded, resulting in splenomegaly with disruption of normal splenic architecture and the presence of hemophagocytes, which are findings reminiscent of HLH. Notably, a substantial fraction of patients who received anti-CD22 CAR T cells also experienced biphasic inflammation, with the second phase occurring after the resolution of cytokine release syndrome, resembling clinical manifestations of HLH. Elevated inflammatory cytokines such as IL-1ß and IL-18 and concurrent late CAR T cell expansion characterized the HLH-like syndromes occurring in the murine model and in humans. Thus, a murine model of perforin-deficient CAR T cells recapitulated late-onset inflammatory toxicities occurring in human CAR T cell recipients, providing therapeutically relevant mechanistic insights.

13.
J Crit Care ; 58: 58-64, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32361219

RESUMO

PURPOSE: A task force of experts from 11 United States (US) centers, sought to describe practices for managing chimeric antigen receptor (CAR) T-cell toxicity in the intensive care unit (ICU). MATERIALS AND METHODS: Between June-July 2019, a survey was electronically distributed to 11 centers. The survey addressed: CAR products, toxicities, targeted treatments, management practices and interventions in the ICU. RESULTS: Most centers (82%) had experience with commercial and non-FDA approved CAR products. Criteria for ICU admission varied between centers for patients with Cytokine Release Syndrome (CRS) but were similar for Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS). Practices for vasopressor support, neurotoxicity and electroencephalogram monitoring, use of prophylactic anti-epileptic drugs and tocilizumab were comparable. In contrast, fluid resuscitation, respiratory support, methods of surveillance and management of cerebral edema, use of corticosteroid and other anti-cytokine therapies varied between centers. CONCLUSIONS: This survey identified areas of investigation that could improve outcomes in CAR T-cell recipients such as fluid and vasopressor selection in CRS, management of respiratory failure, and less common complications such as hemophagocytic lymphohistiocytosis, infections and stroke. The variability in specific treatments for CAR T-cell toxicities, needs to be considered when designing future outcome studies of critically ill CAR T-cell patients.

14.
Bone Marrow Transplant ; 55(11): 2121-2131, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32355289

RESUMO

Pre-harvest autologous blood collection from bone marrow (BM) donors is performed to meet potential post-operative transfusion needs. This study examines the impact of autologous blood transfusion on BM donor's health and safety. The study included first-time unrelated BM donors from the United States whose BM harvest was facilitated by the National Marrow Donor Program (NMDP) centers between 2006 and 2017. Examination of 7024 BM donors revealed that 60% received at least one unit of autologous blood. The donors who received autologous blood were older, had lower hemoglobin pre-harvest, underwent longer duration of anesthesia, and higher volume BM harvest. Only donors who underwent high-volume BM harvest, defined as a BM harvest volume >27% of donor's blood volume, benefited from autologous transfusion. After a high-volume BM harvest, autologous blood transfusion was shown to decrease grade 2 to 4 collection-associated toxicities within 48 h of BM donation (p = 0.010) and shorten the time to donor-reported "complete" recovery from donation-associated symptoms (p < 0.001). Therefore, autologous transfusion could be avoided as support of marrow donation in the majority of unrelated BM donors and should be limited to cases where the planned BM harvest volume is expected to exceed 27% of donor's blood volume.

15.
J Clin Oncol ; 38(17): 1938-1950, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32286905

RESUMO

PURPOSE: Patients with B-cell acute lymphoblastic leukemia who experience relapse after or are resistant to CD19-targeted immunotherapies have limited treatment options. Targeting CD22, an alternative B-cell antigen, represents an alternate strategy. We report outcomes on the largest patient cohort treated with CD22 chimeric antigen receptor (CAR) T cells. PATIENTS AND METHODS: We conducted a single-center, phase I, 3 + 3 dose-escalation trial with a large expansion cohort that tested CD22-targeted CAR T cells for children and young adults with relapsed/refractory CD22+ malignancies. Primary objectives were to assess the safety, toxicity, and feasibility. Secondary objectives included efficacy, CD22 CAR T-cell persistence, and cytokine profiling. RESULTS: Fifty-eight participants were infused; 51 (87.9%) after prior CD19-targeted therapy. Cytokine release syndrome occurred in 50 participants (86.2%) and was grade 1-2 in 45 (90%). Symptoms of neurotoxicity were minimal and transient. Hemophagocytic lymphohistiocytosis-like manifestations were seen in 19/58 (32.8%) of subjects, prompting utilization of anakinra. CD4/CD8 T-cell selection of the apheresis product improved CAR T-cell manufacturing feasibility as well as heightened inflammatory toxicities, leading to dose de-escalation. The complete remission rate was 70%. The median overall survival was 13.4 months (95% CI, 7.7 to 20.3 months). Among those who achieved a complete response, the median relapse-free survival was 6.0 months (95% CI, 4.1 to 6.5 months). Thirteen participants proceeded to stem-cell transplantation. CONCLUSION: In the largest experience of CD22 CAR T-cells to our knowledge, we provide novel information on the impact of manufacturing changes on clinical outcomes and report on unique CD22 CAR T-cell toxicities and toxicity mitigation strategies. The remission induction rate supports further development of CD22 CAR T cells as a therapeutic option in patients resistant to CD19-targeted immunotherapy.

17.
Pediatr Blood Cancer ; 67(5): e28249, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32159278

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). However, this new paradigm has introduced unique considerations specific to the patients receiving CAR T-cell therapy, including prognostic uncertainty, symptom management, and psychosocial support. With increasing availability, there is a growing need for evidence-based recommendations that address the specific psychosocial needs of the children who receive CAR T-cell therapy and their families. To guide and standardize the psychosocial care offered for patients receiving CAR T-cell therapy, we propose the following recommendations for addressing psychosocial support.


Assuntos
Imunoterapia Adotiva/psicologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/psicologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos Quiméricos , Criança , Humanos
19.
Blood Adv ; 4(4): 706-716, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32092138

RESUMO

There are limited data on the effect of donor body mass index (BMI) on peripheral blood stem cell (PBSC) mobilization response to granulocyte colony-stimulating factor (G-CSF), especially in unrelated donors. Obesity has been associated with persistent leukocytosis, elevated circulating progenitor cells, and enhanced stem cell mobilization. Therefore, we hypothesized that adequate collection of CD34+ cells may be achieved with lower doses (per kilogram of body weight) of G-CSF in donors with higher BMI compared with donors with lower BMI. Using the Center for International Blood and Marrow Transplant Research database, we evaluated the impact of donor BMI on G-CSF-mobilized PBSC yield in healthy unrelated donors. We examined 20 884 PBSC donations collected at National Marrow Donor Program centers between 2006 and 2016. We found significantly higher collection yields in obese and severely obese donors compared with normal and overweight donors. An increase in average daily G-CSF dose was associated with an increase in stem cell yield in donors with normal or overweight BMI. In contrast, an increase in average daily G-CSF dose beyond 780 µg per day in obese and 900 µg per day in severely obese donors did not increase cell yield. Pain and toxicities were assessed at baseline, during G-CSF administration, and postcollection. Obesity was associated with higher levels of self-reported donation-related pain and toxicities in the pericollection and early postdonation recovery periods. This study suggests a maximum effective G-CSF dose for PBSC mobilization in obese and severely obese donors, beyond which higher doses of G-CSF add no increased yield.

20.
Nat Immunol ; 21(3): 254-258, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32094649

RESUMO

Women have been at the forefront of tremendous achievements in immunology in the past decade. However, disparities still exist, limiting upward potential and further advancements. As four NIH intramural women scientists who care deeply about scientific progress and the progress of women in our field, we review ongoing challenges and discuss potential approaches to help advance the promotion of women in the sciences.


Assuntos
Alergia e Imunologia/tendências , Sexismo/tendências , Direitos da Mulher/tendências , Pesquisa Biomédica/tendências , Mobilidade Ocupacional , Feminino , História do Século XXI , Humanos , Tutoria/tendências , National Institutes of Health (U.S.) , Estados Unidos
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