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1.
Bioorg Chem ; : 103460, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31791682

RESUMO

One-pot synthesis of caprylic, lauric and palmitic acid mono- and diesters of trehalose was catalyzed by the lipase Fermase CALB™ 10000. An optimized molar conversion of 35% of trehalose to its palmitate esters was obtained in acetone at 60 °C with a trehalose:palmitic acid molar ratio of 1:5 in 4 h. Trehalose fatty acid esters (THFAE) were purified by column chromatography and characterized using TLC, HPTLC, HR-MS, ATR-FTIR, and differential scanning calorimetry. THFAE were studied for their antimicrobial potential against four bacterial, and two fungal species. Trehalose monolaurate and trehalose dicaprylate demonstrated MIC of 0.45 mM and 16 mM against Pseudomonas aeruginosa and Escherichia coli, respectively. Trehalose monocaprylate showed the highest inhibition of biofilm forming property against Staphylococcus aureus (86.25%) at 99.2 mM and trehalose dipalmitate had lowest IC50 of 13.23 mM. Furthermore, their anti-inflammatory property was studied in vitro using 15-LOX inhibition assay and human red blood cell membrane stabilization assay. In the confirmatory in vivo tests using carrageenan-induced rat paw edema assay, inflammation in disease control group reached up to 63% as against 32% and 20% for trehalose dilaurate and diclofenac treated groups, respectively. THFAE can hence find potential applications in pharmaceuticals, functional foods, and nutraceuticals.

2.
Blood Adv ; 3(21): 3393-3405, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714961

RESUMO

Detection of minimal residual disease (MRD) pre- and post-hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) has been associated with relapse and poor survival. Published studies have had insufficient numbers to: (1) compare the prognostic value of pre-HCT and post-HCT MRD; (2) determine clinical factors post-HCT associated with better outcomes in MRD+ patients; and (3) use MRD and other clinical factors to develop and validate a prognostic model for relapse in pediatric patients with ALL who undergo allogeneic HCT. To address these issues, we assembled an international database including sibling (n = 191), unrelated (n = 259), mismatched (n = 56), and cord blood (n = 110) grafts given after myeloablative conditioning. Although high and very high MRD pre-HCT were significant predictors in univariate analysis, with bivariate analysis using MRD pre-HCT and post-HCT, MRD pre-HCT at any level was less predictive than even low-level MRD post-HCT. Patients with MRD pre-HCT must become MRD low/negative at 1 to 2 months and negative within 3 to 6 months after HCT for successful therapy. Factors associated with improved outcome of patients with detectable MRD post-HCT included acute graft-versus-host disease. We derived a risk score with an MRD cohort from Europe, North America, and Australia using negative predictive characteristics (late disease status, non-total body irradiation regimen, and MRD [high, very high]) defining good, intermediate, and poor risk groups with 2-year cumulative incidences of relapse of 21%, 38%, and 47%, respectively. We validated the score in a second, more contemporaneous cohort and noted 2-year cumulative incidences of relapse of 13%, 26%, and 47% (P < .001) for the defined risk groups.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31493539

RESUMO

Allogeneic blood or marrow transplantation (BMT) is a potentially curative therapy for patients with primary immunodeficiency (PID). Safe and effective reduced-intensity conditioning (RIC) approaches that are associated with low toxicity, use alternative donors, and afford good immune reconstitution are needed to advance the field. Twenty PID patients, ranging in age from 4 to 58 years, were treated on a prospective clinical trial of a novel, radiation-free and serotherapy-free RIC, T-cell-replete BMT approach using pentostatin, low-dose cyclophosphamide, and busulfan for conditioning with post-transplantation cyclophosphamide-based graft-versus-host-disease (GVHD) prophylaxis. This was a high-risk cohort with a median hematopoietic cell transplantation comorbidity index of 3. With median follow-up of survivors of 1.9 years, 1-year overall survival was 90% and grade III to IV acute GVHD-free, graft-failure-free survival was 80% at day +180. Graft failure incidence was 10%. Split chimerism was frequently observed at early post-BMT timepoints, with a lower percentage of donor T cells, which gradually increased by day +60. The cumulative incidences of grade II to IV and grade III to IV acute GVHD (aGVHD) were 15% and 5%, respectively. All aGVHD was steroid responsive. No patients developed chronic GVHD. Few significant organ toxicities were observed. Evidence of phenotype reversal was observed for all engrafted patients, even those with significantly mixed chimerism (n = 2) or with unknown underlying genetic defect (n = 3). All 6 patients with pre-BMT malignancies or lymphoproliferative disorders remain in remission. Most patients have discontinued immunoglobulin replacement. All survivors are off immunosuppression for GVHD prophylaxis or treatment. This novel RIC BMT approach for patients with PID has yielded promising results, even for high-risk patients.

5.
J Clin Immunol ; 39(6): 592-595, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31267431

RESUMO

Mutations in Dedicator of cytokinesis 8 (DOCK8) are a rare cause of combined immunodeficiency associated with atopy, infectious susceptibility, and risk for malignancy. We describe a 22-year-old male with a diagnosis of B cell lymphoblastic leukemia followed by Epstein-Barr virus (EBV)-associated diffuse large B cell lymphoma (DLBCL) with compound heterozygous mutations in DOCK8 and normal intracellular DOCK8 protein expression. Here, B cell lymphoblastic leukemia followed by EBV-associated DLBCL led to the discovery of DOCK8 deficiency. For instances of high clinical suspicion despite normal DOCK8 protein expression, additional functional testing is critical to make a diagnosis. Understanding the spectrum of DOCK8 mutants and their phenotypes will improve our understanding of DOCK8 deficiency.

6.
Immunol Rev ; 290(1): 39-59, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31355492

RESUMO

By increasing disease-free survival and offering the potential for long-term cure, chimeric antigen receptor (CAR) T-cell therapy has dramatically expanded therapeutic options among those with high-risk B-cell malignancies. As CAR T-cell utilization evolves however, novel challenges are generated. These include determining how to optimally integrate CAR T cells into standard of care and overcoming mechanisms of resistance to CAR T-cell therapy, such as evolutionary stress induced on cancer cells leading to immunophenotypic changes that allow leukemia to evade this targeted therapy. Compounding these challenges are the limited ability to determine differences between various CAR T-cell constructs, understanding the generalizability of trial outcomes from multiple sites utilizing unique CAR manufacturing strategies, and comparing distinct criteria for toxicity grading while defining optimal management. Additionally, as understanding of CAR behavior in humans has developed, strategies have appropriately evolved to proactively mitigate toxicities. These challenges offer complimentary insights and guide next steps to enhance the efficacy of this novel therapeutic modality. With a focus on B-cell malignancies as the paradigm for effective CAR T-cell therapy, this review describes advances in the field as well as current challenges and future directions.

7.
Mol Ther ; 27(7): 1275-1285, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31178392

RESUMO

As clinical applications for chimeric antigen receptor T cell (CART) therapy extend beyond early phase trials, commercial manufacture incorporating cryopreservation steps becomes a logistical necessity. The effect of cryopreservation on CART characteristics is unclear. We retrospectively evaluated the effect of cryopreservation on product release criteria and in vivo characteristics in 158 autologous CART products from 6 single-center clinical trials. Further, from 3 healthy donor manufacturing runs, we prospectively identified differentially expressed cell surface markers and gene signatures among fresh versus cryopreserved CARTs. Within 2 days of culture initiation, cell viability of the starting fraction (peripheral blood mononuclear cells [PBMNCs]) decreased significantly in the cryo-thawed arm compared to the fresh arm. Despite this, PBMNC cryopreservation did not affect final CART fold expansion, transduction efficiency, CD3%, or CD4:CD8 ratios. In vivo CART persistence and clinical responses did not differ among fresh and cryopreserved final products. In healthy donors, compared to fresh CARTs, early apoptotic cell-surface markers were significantly elevated in cryo-thawed CARTs. Cryo-thawed CARTs also demonstrated significantly elevated expression of mitochondrial dysfunction, apoptosis signaling, and cell cycle damage pathways. Cryopreservation during CART manufacture is a viable strategy, based on standard product release parameters. The clinical impact of cryopreservation-related subtle micro-cellular damage needs further study.

8.
Bone Marrow Transplant ; 54(11): 1868-1880, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31092900

RESUMO

On August 30, 2017, the U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor-T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.

9.
Clin Cancer Res ; 25(17): 5329-5341, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31110075

RESUMO

PURPOSE: Chimeric antigen receptor T-cell (CART) therapy targeting CD22 induces remission in 70% of patients with relapsed/refractory acute lymphoblastic leukemia (ALL). However, the majority of post-CD22 CART remissions are short and associated with reduction in CD22 expression. We evaluate the implications of low antigen density on the activity of CD22 CART and propose mechanisms to overcome antigen escape. EXPERIMENTAL DESIGN: Using ALL cell lines with variable CD22 expression, we evaluate the cytokine profile, cytotoxicity, and in vivo CART functionality in the setting of low CD22 expression. We develop a high-affinity CD22 chimeric antigen receptor (CAR) as an approach to improve CAR sensitivity. We also assess Bryostatin1, a therapeutically relevant agent, to upregulate CD22 and improve CAR functionality. RESULTS: We demonstrate that low CD22 expression negatively impacts in vitro and in vivo CD22 CART functionality and impairs in vivo CART persistence. Moreover, low antigen expression on leukemic cells increases naïve phenotype of persisting CART. Increasing CAR affinity does not improve response to low-antigen leukemia. Bryostatin1 upregulates CD22 on leukemia and lymphoma cell lines for 1 week following single-dose exposure, and improves CART functionality and in vivo persistence. While Bryostatin1 attenuates IFNγ production by CART, overall in vitro and in vivo CART cytotoxicity is not adversely affected. Finally, administration of Bryostain1 with CD22 CAR results in longer duration of in vivo response. CONCLUSIONS: We demonstrate that target antigen modulation is a promising strategy to improve CD22 CAR efficacy and remission durability in patients with leukemia and lymphoma.See related commentary by Guedan and Delgado, p. 5188.


Assuntos
Linfoma , Linfócitos T/imunologia , Antígenos CD19 , Humanos , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos
10.
Bone Marrow Transplant ; 54(11): 1780-1788, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30971776

RESUMO

Understanding the potential emotional and psychological risks of pediatric sibling HSC donation is an area of research that remains in its infancy. A cross-sectional survey was distributed electronically to directors at all CIBMTR and EBMT centers to describe current transplant center practices for obtaining assent, preparation for the physical/emotional experiences of donation, and monitoring the post-donation well-being of pediatric donors (<18 years of age). Respondents were 45/91 (49%) and 66/144 (46%) of CIBMTR and EBMT centers, respectively. Although 78% of centers reported having a mechanism in place to ensure donor free assent, centers also reported only limited assessment of psychosocial suitability to manage the emotional risks of donation. More than half of centers reported no psychosocial follow-up assessment post-donation. Few centers have policies in place to address donor psychological needs. Future investigations should include medical and psychosocial outcomes following full integration of comprehensive psychosocial screening and surveillance of pediatric donors.

11.
Leukemia ; 33(4): 1061-1062, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30842605

RESUMO

We thank the research coordinators and following physicians at pediatric cancer centers for contributing data to this project: Prashant Hiwarkar and Jayashree Motwani, Birmingham Women's and Children's Hospital, UK; Kelly Malone, Children's Hospital of Colorado, USA; Mylene Bassal, Children's Hospital of Eastern Ontario, Canada; Yoav Messinger and Joanna Perkins, Children's Hospital of Minnesota, USA; Van Huynh, Children's Hospital of Orange County, USA; Richard Ho, Children's Hospital at Vanderbilt, USA; Joanne Chuah and Jessa Morales, Children's Hospital at Westmead, Australia; Donald Wells, Dell Children's Hospital, USA; Nicolas Boissel, Hospital Saint-Louis, France; Tannie Huang, Kaiser Permanente, USA; Stacey Marjerrison, McMaster Children's Hospital, Canada; William Carroll and Joanna Pierro, New York University Langone Medical Center, USA; Ajay Vora, Sheffield Children's Hospital, UK; Donna Lancaster, The Royal Marsden Hospital, UK; Lucie Srámková, University Hospital Motol, Czech Republic; Chatchawin Assanasen, University of Texas Health Science Center, San Antonio, USA; Rupert Handgretinger, University of Tübingen, Germany.

12.
Nat Rev Clin Oncol ; 16(6): 372-385, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30837712

RESUMO

The successes with chimeric antigen receptor (CAR) T cell therapy in early clinical trials involving patients with pre-B cell acute lymphoblastic leukaemia (ALL) or B cell lymphomas have revolutionized anticancer therapy, providing a potentially curative option for patients who are refractory to standard treatments. These trials resulted in rapid FDA approvals of anti-CD19 CAR T cell products for both ALL and certain types of B cell lymphoma - the first approved gene therapies in the USA. However, growing experience with these agents has revealed that remissions will be brief in a substantial number of patients owing to poor CAR T cell persistence and/or cancer cell resistance resulting from antigen loss or modulation. Furthermore, the initial experience with CAR T cells has highlighted challenges associated with manufacturing a patient-specific therapy. Understanding the limitations of CAR T cell therapy will be critical to realizing the full potential of this novel treatment approach. Herein, we discuss the factors that can preclude durable remissions following CAR T cell therapy, with a primary focus on the resistance mechanisms that underlie disease relapse. We also provide an overview of potential strategies to overcome these obstacles in an effort to more effectively incorporate this unique therapeutic strategy into standard treatment paradigms.


Assuntos
Imunoterapia Adotiva/métodos , Linfoma de Células B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Antígenos CD19/imunologia , Ensaios Clínicos como Assunto , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Humanos , Linfoma de Células B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Prevenção Secundária
13.
Pediatr Blood Cancer ; 66(7): e27732, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30900813

RESUMO

Invasive fusariosis (IF) most commonly occurs in patients with hematologic malignancies and severe neutropenia, particularly during concomitant corticosteroid use. Breakthrough infections can occur in high-risk patients despite Aspergillus-active antifungal prophylaxis. We describe a patient with rapid acute lymphoblastic leukemia (ALL) progression who presented with multifocal skin nodules thought to be choloromatous disease. These lesions were ultimately diagnosed as IF and the patient had two simultaneously active disease processes. This case highlights the importance of pathologic diagnosis of new skin lesions in ALL patients, even during leukemia progression, and demonstrates that IF can occur despite normal neutrophil counts and Aspergillus-active prophylaxis.

14.
Transplantation ; 103(10): 2144-2149, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30720689

RESUMO

BACKGROUND: An 11-year-old girl with dedicator of cytokinesis 8 (DOCK8) deficiency was proposed for potentially curative hematopoietic stem cell transplantation (HSCT), the donor being her haploidentical mother. However, end-stage liver disease caused by chronic Cryptosporidium infection required liver transplantation before HSCT. METHODS: Consequently, a staged approach of a sequential liver transplant followed by a HSCT was planned with her mother as the donor for both liver and HSCT. RESULTS: The patient successfully underwent a left-lobe orthotopic liver transplant; however, she developed a biliary leak delaying the HSCT. Notably, the recipient demonstrated 3% donor lymphocyte chimerism in her peripheral blood immediately before HSCT. Haploidentical-related donor HSCT performed 2 months after liver transplantation was complicated by the development of acyclovir-resistant herpes simplex virus viremia, primary graft failure, and sinusoidal obstruction syndrome. The patient died from sinusoidal obstruction syndrome-associated multiorgan failure with Candida sepsis on day +40 following HSCT. CONCLUSIONS: We discuss the many considerations inherent to planning for HSCT preceded by liver transplant in patients with primary immunodeficiencies, including the role of prolonged immunosuppression and the risk of infection before immune reconstitution. We also discuss the implications of potential recipient sensitization against donor stem cells precipitated by exposure of the recipient to the donor lymphocytes from the transplanted organ.

15.
Biol Blood Marrow Transplant ; 25(7): 1325-1330, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30716454

RESUMO

Bone marrow (BM) is an essential source of hematopoietic stem cell grafts for many allogeneic hematopoietic cell transplant (HCT) recipients, including adult patients (for specific diseases and transplantation strategies) and the majority of pediatric recipient. However, since the advent of granulocyte colony-stimulating factor-mobilized peripheral blood stem cell (PBSC) grafts, there has been a significant decrease in the use of BM in HCT, thought to be due mainly to the increased logistical challenges in harvesting BM compared with PBSCs, as well as generally no significant survival advantage of BM over PBSCs. The decreased frequency of collection has the potential to impact the quality of BM harvests. In this study, we examined >15,000 BM donations collected at National Marrow Donor Program centers between 1994 and 2016 and found a significant decline in the quality of BM products, as defined by the concentration of total nucleated cells (TNCs). The mean TNC concentration in BM donations dropped from 21.8 × 106 cells/mL in the earliest era (1994 to 1996) to 18.7 × 106 cells/mL in the most recent era (2012 to 2016) (means ratio, .83; P < .001). This decline in BM quality was seen despite the selection of more donors perceived to be optimal (eg, younger and male). Multivariate regression analysis showed that higher-volume centers (performing >30 collections per era) had better-quality harvests with higher concentrations of TNCs collected. In conclusion, we have identified a significant decrease in the quality of BM collections over time, and lower-volume collection centers had poorer-quality harvests. In this analysis, we could not elucidate the direct cause for this finding, suggesting the need for further studies to investigate the key factors responsible and to explore the impact on transplant recipients.

16.
Biol Blood Marrow Transplant ; 25(3): e76-e85, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30576834

RESUMO

On August 30, 2017 the US Food and Drug Administration approved tisagenlecleucel (Kymriah; Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present, ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring, and disease assessments. To address these issues experts representing the American Society for Blood and Marrow Transplant, the European Society for Blood and Marrow Transplantation, the International Society of Cell and Gene Therapy, and the Foundation for the Accreditation of Cellular Therapy formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.

17.
Artigo em Inglês | MEDLINE | ID: mdl-30391550

RESUMO

BACKGROUND: Biallelic variations in the DOCK8 gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8 deficient patients. RESULTS: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range: 0.7-27.2) between 1995 and 2015. After median follow-up of 26 months (3-135), 68 of 81 patients are alive (84%). Severe acute (III-IV) or chronic graft versus host disease (GVHD) occurred in 11% and 10% respectively. Causes of death wereinfections (n=5), GVHD (5), multi-organ failure (2) and pre-existent lymphoma (1). Survival after matched related (n=40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared to fully myeloablative busulfan-based regimens (97% vs. 78%; p=0.049). 96% of patients aged <8 years at HSCT survived, compared to 78% of those ≥8 years (p=0.06). Of 73 patients with chimerism data available, 65 (89%) had >90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections and Mollusca resolved better than food allergies or failure to thrive. CONCLUSION: HSCT is curative in most DOCK8 deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced toxicity regimen may offer the best chance for survival.

19.
Artigo em Inglês | MEDLINE | ID: mdl-30342913

RESUMO

Human cytomegalovirus (CMV) infection and disease remains a significant cause of morbidity and mortality for hematopoietic cell transplantation (HCT) recipients. Disruption of or weak reconstitution of virus-specific cellular immune function, such as with certain HCT approaches, poses significant risk for CMV-related complications. The incidence of and risk factors for CMV infection and the nature of CMV disease were evaluated retrospectively among 356 consecutive HCT recipients transplanted at the National Institutes of Health using all graft sources, including bone marrow, peripheral blood stem cell (PBSC), and umbilical cord blood (UCB), and a range of in vivo and ex vivo approaches for graft-versus-host disease (GVHD) prophylaxis. The cumulative incidence of CMV infection was higher for CMV-seropositive recipients at 33%, regardless of donor CMV serostatus. Patients transplanted with CMV-seropositive donors had a significantly shorter duration of antiviral therapy. Among graft sources UCB was associated with the highest cumulative incidence of CMV infection at 65% and significantly longer treatment duration at a median of 36 days, whereas PBSC HCT was associated with the lowest incidence at 26% and the shortest CMV treatment duration at a median of 21 days. There were significant differences in the cumulative incidence of CMV infection by T cell manipulation strategy when systemic steroids were included as a risk-modifying event. Over one-third of CMV infections occurred in the setting of systemic steroid administration. CMV disease occurred in 5% of HCT recipients, with 70% of cases in the setting of treatment for GVHD. Although factors related to serostatus, graft source, and GVHD prophylaxis were associated with varied CMV infection incidence, unplanned post-HCT corticosteroid therapy contributed greatly to the incidence of both CMV infection and disease across HCT approaches, highlighting this post-HCT intervention as a key time to potentially tailor the approach to monitoring, preemptive therapy, and even prophylaxis.

20.
Leukemia ; 2018 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-30267011

RESUMO

Although inotuzumab ozogamicin (InO) is recognized as an effective agent in relapsed acute lymphoblastic leukemia (ALL) in adults, data on safety and efficacy in pediatric patients are scarce. We report the use of InO in 51 children with relapsed/refractory ALL treated in the compassionate use program. In this heavily pretreated cohort, complete remission was achieved in 67% of patients with overt marrow disease. The majority (71%) of responders were negative for minimal residual disease. Responses were observed irrespective of cytogenetic subtype or number or type of prior treatment regimens. InO was well-tolerated; grade 3 hepatic transaminitis or hyperbilirubinemia were noted in 6 (12%) and grade 3/4 infections in 11 (22%) patients. No patient developed sinusoidal obstruction syndrome (SOS) during InO therapy; however, 11 of 21 (52%) patients who underwent hematopoietic stem cell transplantation (HSCT) following InO developed SOS. Downregulation of surface CD22 was detected as a possible escape mechanism in three patients who developed a subsequent relapse after InO. We conclude that InO is a well-tolerated, effective therapy for children with relapsed ALL and prospective studies are warranted. Identification of risk factors for developing post-HSCT SOS and strategies to mitigate this risk are ongoing.

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