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1.
Cell Rep Med ; 4(11): 101259, 2023 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-37913777

RESUMO

Umbilical cord blood transplantation is a life-saving treatment for malignant and non-malignant hematologic disorders. It remains unclear how long cryopreserved units remain functional, and the length of cryopreservation is often used as a criterion to exclude older units. We demonstrate that long-term cryopreserved cord blood retains similar numbers of hematopoietic stem and progenitor cells compared with fresh and recently cryopreserved cord blood units. Long-term cryopreserved units contain highly functional cells, yielding robust engraftment in mouse transplantation models. We also leverage differences between units to examine gene programs associated with better engraftment. Transcriptomic analyses reveal that gene programs associated with lineage determination and oxidative stress are enriched in high engrafting cord blood, revealing potential molecular markers to be used as potency markers for cord blood unit selection regardless of length of cryopreservation. In summary, cord blood units cryopreserved for extended periods retain engrafting potential and can potentially be used for patient treatment.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Animais , Camundongos , Humanos , Sangue Fetal , Criopreservação
2.
Clin Cancer Res ; 29(18): 3622-3632, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37439808

RESUMO

PURPOSE: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by systemic symptoms, cytopenias, organomegaly, and bone marrow fibrosis. JAK2 inhibitors afford symptom and spleen burden reduction but do not alter the disease course and frequently lead to thrombocytopenia. TGFß, a pleiotropic cytokine elaborated by the MF clone, negatively regulates normal hematopoiesis, downregulates antitumor immunity, and promotes bone marrow fibrosis. Our group previously showed that AVID200, a potent and selective TGFß 1/3 trap, reduced TGFß1-induced proliferation of human mesenchymal stromal cells, phosphorylation of SMAD2, and collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PC) with wild-type JAK2 rather than JAK2V617F. PATIENTS AND METHODS: We conducted an investigator-initiated, multicenter, phase Ib trial of AVID200 monotherapy in 21 patients with advanced MF. RESULTS: No dose-limiting toxicity was identified at the three dose levels tested, and grade 3/4 anemia and thrombocytopenia occurred in 28.6% and 19.0% of treated patients, respectively. After six cycles of therapy, two patients attained a clinical benefit by IWG-MRT criteria. Spleen and symptom benefits were observed across treatment cycles. Unlike other MF-directed therapies, increases in platelet counts were noted in 81% of treated patients with three patients achieving normalization. Treatment with AVID200 resulted in potent suppression of plasma TGFß1 levels and pSMAD2 in MF cells. CONCLUSIONS: AVID200 is a well-tolerated, rational, therapeutic agent for the treatment of patients with MF and should be evaluated further in patients with thrombocytopenic MF in combination with agents that target aberrant MF intracellular signaling pathways.


Assuntos
Transtornos Mieloproliferativos , Mielofibrose Primária , Trombocitopenia , Humanos , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/metabolismo , Janus Quinase 2/metabolismo , Citocinas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Trombocitopenia/induzido quimicamente
3.
Cancer Res Commun ; 3(5): 943-951, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37377894

RESUMO

Interferons (IFNs) are cytokines with potent antineoplastic and antiviral properties. IFNα has significant clinical activity in the treatment of myeloproliferative neoplasms (MPN), but the precise mechanisms by which it acts are not well understood. Here, we demonstrate that chromatin assembly factor 1 subunit B (CHAF1B), an Unc-51-like kinase 1 (ULK1)-interactive protein in the nuclear compartment of malignant cells, is overexpressed in patients with MPN. Remarkably, targeted silencing of CHAF1B enhances transcription of IFNα-stimulated genes and promotes IFNα-dependent antineoplastic responses in primary MPN progenitor cells. Taken together, our findings indicate that CHAF1B is a promising newly identified therapeutic target in MPN and that CHAF1B inhibition in combination with IFNα therapy might offer a novel strategy for treating patients with MPN. Significance: Our findings raise the potential for clinical development of drugs targeting CHAF1B to enhance IFN antitumor responses in the treatment of patients with MPN and should have important clinical translational implications for the treatment of MPN and possibly in other malignancies.


Assuntos
Neoplasias da Medula Óssea , Transtornos Mieloproliferativos , Neoplasias , Humanos , Transtornos Mieloproliferativos/tratamento farmacológico , Interferon-alfa/farmacologia , Fator 1 de Modelagem da Cromatina/genética
5.
Cell Host Microbe ; 31(1): 97-111.e12, 2023 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-36347257

RESUMO

Humanity has faced three recent outbreaks of novel betacoronaviruses, emphasizing the need to develop approaches that broadly target coronaviruses. Here, we identify 55 monoclonal antibodies from COVID-19 convalescent donors that bind diverse betacoronavirus spike proteins. Most antibodies targeted an S2 epitope that included the K814 residue and were non-neutralizing. However, 11 antibodies targeting the stem helix neutralized betacoronaviruses from different lineages. Eight antibodies in this group, including the six broadest and most potent neutralizers, were encoded by IGHV1-46 and IGKV3-20. Crystal structures of three antibodies of this class at 1.5-1.75-Å resolution revealed a conserved mode of binding. COV89-22 neutralized SARS-CoV-2 variants of concern including Omicron BA.4/5 and limited disease in Syrian hamsters. Collectively, these findings identify a class of IGHV1-46/IGKV3-20 antibodies that broadly neutralize betacoronaviruses by targeting the stem helix but indicate these antibodies constitute a small fraction of the broadly reactive antibody response to betacoronaviruses after SARS-CoV-2 infection.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Cricetinae , Anticorpos Monoclonais , Surtos de Doenças , Mesocricetus , Anticorpos Antivirais , Anticorpos Neutralizantes , Glicoproteína da Espícula de Coronavírus/genética
6.
Front Immunol ; 13: 1055497, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36569951

RESUMO

Introduction: We previously reported the initial results of a phase II multicenter transplant trial using haploidentical parental donors for children and aolescents with high-risk sickle cell disease achieving excellent survival with exceptionally low rates of graft-versus-host disease and resolution of sickle cell disease symptoms. To investigate human leukocyte antigen (HLA) sensitization, graft characteristics, donor chimerism, and immune reconstitution in these recipients. Methods: CD34 cells were enriched using the CliniMACS® system with a target dose of 10 x 106 CD34+ cells/kg with a peripheral blood mononuclear cell (PBMNC) addback dose of 2x105 CD3/kg in the final product. Pre-transplant HLA antibodies were characterized. Donor chimerism was monitored 1-24 months post-transplant. Comprehensive assessment of immune reconstitution included lymphocyte subsets, plasma cytokines, complement levels, anti-viral T-cell responses, activation markers, and cytokine production. Infections were monitored. Results: HLA antibodies were detected in 7 of 11 (64%) evaluable patients but rarely were against donor antigens. Myeloid engraftment was rapid (100%) at a median of 9 days. At 30 days, donor chimerism was 93-99% and natural killer cell levels were restored. By 60 days, CD19 B cells were normal. CD8 and CD4 T-cells levels were normal by 279 and 365 days, respectively. Activated CD4 and CD8 T-cells were elevated at 100-365 days post-transplant while naïve cells remained below baseline. Tregs were elevated at 100-270 days post-transplant, returning to baseline levels at one year. At one year, C3 and C4 levels were above baseline and CH50 levels were near baseline. At one year, cytokine levels were not significantly different from baseline. Discussion: These results suggest that haploidentical transplantation with CD34-enriched cells and peripheral blood mononuclear cell addback results in rapid engraftment, sustained donor chimerism and broad-based immune reconstitution.


Assuntos
Anemia Falciforme , Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune , Criança , Humanos , Transplante Haploidêntico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucócitos Mononucleares , Quimerismo , Anemia Falciforme/terapia , Citocinas
7.
Blood ; 140(26): 2805-2817, 2022 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-36283106

RESUMO

Myelofibrosis (MF) is a disease associated with high unmet medical needs because allogeneic stem cell transplantation is not an option for most patients, and JAK inhibitors are generally effective for only 2 to 3 years and do not delay disease progression. MF is characterized by dysplastic megakaryocytic hyperplasia and progression to fulminant disease, which is associated with progressively increasing marrow fibrosis. Despite evidence that the inflammatory milieu in MF contributes to disease progression, the specific factors that promote megakaryocyte growth are poorly understood. Here, we analyzed changes in the cytokine profiles of MF mouse models before and after the development of fibrosis, coupled with the analysis of bone marrow populations using single-cell RNA sequencing. We found high interleukin 13 (IL-13) levels in the bone marrow of MF mice. IL-13 promoted the growth of mutant megakaryocytes and induced surface expression of transforming growth factor ß and collagen biosynthesis. Similarly, analysis of samples from patients with MF revealed elevated levels of IL-13 in the plasma and increased IL-13 receptor expression in marrow megakaryocytes. In vivo, IL-13 overexpression promoted disease progression, whereas reducing IL-13/IL-4 signaling reduced several features of the disease, including fibrosis. Finally, we observed an increase in the number of marrow T cells and mast cells, which are known sources of IL-13. Together, our data demonstrate that IL-13 is involved in disease progression in MF and that inhibition of the IL-13/IL-4 signaling pathway might serve as a novel therapeutic target to treat MF.


Assuntos
Transtornos Mieloproliferativos , Neoplasias , Mielofibrose Primária , Camundongos , Animais , Interleucina-13/uso terapêutico , Interleucina-4 , Neoplasias/complicações , Transtornos Mieloproliferativos/complicações , Mielofibrose Primária/genética , Transdução de Sinais/genética , Fibrose , Progressão da Doença
8.
Science ; 377(6607): 728-735, 2022 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-35857439

RESUMO

The potential for future coronavirus outbreaks highlights the need to broadly target this group of pathogens. We used an epitope-agnostic approach to identify six monoclonal antibodies that bind to spike proteins from all seven human-infecting coronaviruses. All six antibodies target the conserved fusion peptide region adjacent to the S2' cleavage site. COV44-62 and COV44-79 broadly neutralize alpha- and betacoronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants BA.2 and BA.4/5, albeit with lower potency than receptor binding domain-specific antibodies. In crystal structures of COV44-62 and COV44-79 antigen-binding fragments with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine residue at the S2' cleavage site. COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings highlight the fusion peptide as a candidate epitope for next-generation coronavirus vaccine development.


Assuntos
Anticorpos Monoclonais , Anticorpos Antivirais , Anticorpos Amplamente Neutralizantes , COVID-19 , Epitopos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/química , Vacinas contra COVID-19/imunologia , Epitopos/química , Epitopos/imunologia , Humanos , Peptídeos/imunologia , Conformação Proteica em alfa-Hélice , Domínios Proteicos , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia
9.
bioRxiv ; 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35441178

RESUMO

The potential for future coronavirus outbreaks highlights the need to develop strategies and tools to broadly target this group of pathogens. Here, using an epitope-agnostic approach, we identified six monoclonal antibodies that bound to spike proteins from all seven human-infecting coronaviruses. Epitope mapping revealed that all six antibodies target the conserved fusion peptide region adjacent to the S2' cleavage site. Two antibodies, COV44-62 and COV44-79, broadly neutralize a range of alpha and beta coronaviruses, including SARS-CoV-2 Omicron subvariants BA.1 and BA.2, albeit with lower potency than RBD-specific antibodies. In crystal structures of Fabs COV44-62 and COV44-79 with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine at the S2' cleavage site. Importantly, COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings identify the fusion peptide as the target of the broadest neutralizing antibodies in an epitope-agnostic screen, highlighting this site as a candidate for next-generation coronavirus vaccine development. One-Sentence Summary: Rare monoclonal antibodies from COVID-19 convalescent individuals broadly neutralize coronaviruses by targeting the fusion peptide.

10.
Nat Commun ; 13(1): 1750, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35365653

RESUMO

Interferons (IFNs) are key initiators and effectors of the immune response against malignant cells and also directly inhibit tumor growth. IFNα is highly effective in the treatment of myeloproliferative neoplasms (MPNs), but the mechanisms of action are unclear and it remains unknown why some patients respond to IFNα and others do not. Here, we identify and characterize a pathway involving PKCδ-dependent phosphorylation of ULK1 on serine residues 341 and 495, required for subsequent activation of p38 MAPK. We show that this pathway is essential for IFN-suppressive effects on primary malignant erythroid precursors from MPN patients, and that increased levels of ULK1 and p38 MAPK correlate with clinical response to IFNα therapy in these patients. We also demonstrate that IFNα treatment induces cleavage/activation of the ULK1-interacting ROCK1/2 proteins in vitro and in vivo, triggering a negative feedback loop that suppresses IFN responses. Overexpression of ROCK1/2 is seen in MPN patients and their genetic or pharmacological inhibition enhances IFN-anti-neoplastic responses in malignant erythroid precursors from MPN patients. These findings suggest the clinical potential of pharmacological inhibition of ROCK1/2 in combination with IFN-therapy for the treatment of MPNs.


Assuntos
Transtornos Mieloproliferativos , Neoplasias , Antivirais/uso terapêutico , Retroalimentação , Humanos , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Neoplasias/tratamento farmacológico , Transdução de Sinais , Quinases Associadas a rho/metabolismo
11.
JCI Insight ; 7(8)2022 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-35259128

RESUMO

Chronic myeloproliferative neoplasms (MPN) frequently evolve to a blast phase (BP) that is almost uniformly resistant to induction chemotherapy or hypomethylating agents. We explored the functional properties, genomic architecture, and cell of origin of MPN-BP initiating cells (IC) using a serial NSG mouse xenograft transplantation model. Transplantation of peripheral blood mononuclear cells (MNC) from 7 of 18 patients resulted in a high degree of leukemic cell chimerism and recreated clinical characteristics of human MPN-BP. The function of MPN-BP ICs was not dependent on the presence of JAK2V617F, a driver mutation associated with the initial underlying MPN. By contrast, multiple MPN-BP IC subclones coexisted within MPN-BP MNCs characterized by different myeloid malignancy gene mutations and cytogenetic abnormalities. MPN-BP ICs in 4 patients exhibited extensive proliferative and self-renewal capacity, as demonstrated by their ability to recapitulate human MPN-BP in serial recipients. These MPN-BP IC subclones underwent extensive continuous clonal competition within individual xenografts and across multiple generations, and their subclonal dynamics were consistent with functional evolution of MPN-BP IC. Finally, we show that MPN-BP ICs originate from not only phenotypically identified hematopoietic stem cells, but also lymphoid-myeloid progenitor cells, which were each characterized by differences in MPN-BP initiating activity and self-renewal capacity.


Assuntos
Crise Blástica , Transtornos Mieloproliferativos , Animais , Células-Tronco Hematopoéticas/patologia , Humanos , Leucócitos Mononucleares/patologia , Camundongos , Mutação , Transtornos Mieloproliferativos/genética
12.
Autoimmun Rev ; 21(5): 103058, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35108619

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease that causes a deficit of pancreatic islet ß cells. Millions of individuals worldwide have T1D, and its incidence increases annually. Recent clinical trials have highlighted the limits of conventional immunotherapy in T1D and underscore the need for novel treatments that not only overcome multiple immune dysfunctions, but also help restore islet ß-cell function. To address these two key issues, we have developed a unique and novel procedure designated the Stem Cell Educator therapy, based on the immune education by cord-blood-derived multipotent stem cells (CB-SC). Over the last 10 years, this technology has been evaluated through international multi-center clinical studies, which have demonstrated its clinical safety and efficacy in T1D and other autoimmune diseases. Mechanistic studies revealed that Educator therapy could fundamentally correct the autoimmunity and induce immune tolerance through multiple molecular and cellular mechanisms such as the expression of a master transcription factor autoimmune regulator (AIRE) in CB-SC for T-cell modulation, an expression of Galectin-9 on CB-SC to suppress activated B cells, and secretion of CB-SC-derived exosomes to polarize human blood monocytes/macrophages into type 2 macrophages. Educator therapy is the leading immunotherapy to date to safely and efficiently correct autoimmunity and restore ß cell function in T1D patients.


Assuntos
Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Autoimunidade , Diabetes Mellitus Tipo 1/terapia , Sangue Fetal/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Células-Tronco
13.
Blood ; 139(19): 2931-2941, 2022 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-35007321

RESUMO

The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.


Assuntos
Policitemia Vera , Trombocitemia Essencial , Trombose , Progressão da Doença , Humanos , Hidroxiureia/efeitos adversos , Interferon-alfa/efeitos adversos , Policitemia Vera/tratamento farmacológico , Policitemia Vera/genética , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/genética , Trombose/induzido quimicamente , Trombose/prevenção & controle
14.
Sci Transl Med ; 13(616): eabj5413, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34519517

RESUMO

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of existing vaccines and therapeutic antibodies and underscores the need for additional antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells collected from patients with coronavirus disease 2019. The three most potent antibodies targeted distinct regions of the receptor binding domain (RBD), and all three neutralized the SARS-CoV-2 Alpha and Beta variants. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the angiotensin-converting enzyme 2 receptor, and has limited contact with key variant residues K417, E484, and N501. We designed bispecific antibodies by combining nonoverlapping specificities and identified five bispecific antibodies that inhibit SARS-CoV-2 infection at concentrations of less than 1 ng/ml. Through a distinct mode of action, three bispecific antibodies cross-linked adjacent spike proteins using dual N-terminal domain­RBD specificities. One bispecific antibody was greater than 100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a dose of 2.5 mg/kg. Two bispecific antibodies in our panel comparably neutralized the Alpha, Beta, Gamma, and Delta variants and wild-type virus. Furthermore, a bispecific antibody that neutralized the Beta variant protected hamsters against SARS-CoV-2 expressing the E484K mutation. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.


Assuntos
Anticorpos Biespecíficos , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Biespecíficos/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19 , Humanos , SARS-CoV-2
16.
bioRxiv ; 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33821267

RESUMO

The emergence of SARS-CoV-2 variants that threaten the efficacy of existing vaccines and therapeutic antibodies underscores the urgent need for new antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells of COVID-19 patients. The three most potent antibodies targeted distinct regions of the RBD, and all three neutralized the SARS-CoV-2 variants B.1.1.7 and B.1.351. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the ACE2 receptor, and has limited contact with key variant residues K417, E484 and N501. We designed bispecific antibodies by combining non-overlapping specificities and identified five ultrapotent bispecific antibodies that inhibit authentic SARS-CoV-2 infection at concentrations of <1 ng/mL. Through a novel mode of action three bispecific antibodies cross-linked adjacent spike proteins using dual NTD/RBD specificities. One bispecific antibody was >100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a 2.5 mg/kg dose. Notably, six of nine bispecific antibodies neutralized B.1.1.7, B.1.351 and the wild-type virus with comparable potency, despite partial or complete loss of activity of at least one parent monoclonal antibody against B.1.351. Furthermore, a bispecific antibody that neutralized B.1.351 protected against SARS-CoV-2 expressing the crucial E484K mutation in the hamster model. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.

17.
Blood Adv ; 4(20): 5246-5256, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33104796

RESUMO

Myeloproliferative neoplasms (MPN) that have evolved into accelerated or blast phase disease (MPN-AP/BP) have poor outcomes with limited treatment options and therefore represent an urgent unmet need. We have previously demonstrated in a multicenter, phase 1 trial conducted through the Myeloproliferative Neoplasms Research Consortium that the combination of ruxolitinib and decitabine is safe and tolerable and is associated with a favorable overall survival (OS). In this phase 2 trial, 25 patients with MPN-AP/BP were treated at the recommended phase 2 dose of ruxolitinib 25 mg twice daily for the induction cycle followed by 10 mg twice daily for subsequent cycles in combination with decitabine 20 mg/m2 for 5 consecutive days in a 28-day cycle. Nineteen patients died during the study follow-up. The median OS for all patients on study was 9.5 months (95% confidence interval, 4.3-12.0). Overall response rate (complete remission + incomplete platelet recovery + partial remission) was 11/25 (44%) and response was not associated with improved survival. We conclude that the combination of decitabine and ruxolitinib was well tolerated, demonstrated favorable OS, and represents a therapeutic option for this high-risk patient population. This trial was registered at www.clinicaltrials.gov as #NCT02076191.


Assuntos
Crise Blástica , Pirazóis , Crise Blástica/tratamento farmacológico , Decitabina/uso terapêutico , Humanos , Nitrilas , Pirazóis/uso terapêutico , Pirimidinas , Resultado do Tratamento
19.
Transfusion ; 60(1): 133-143, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31756000

RESUMO

BACKGROUND: Cellular therapies using engineered T cells, haploidentical transplants, and autologous gene therapy are increasing. Specified CD3+ or high CD34+ doses are typically required for subsequent manufacturing, manipulation, or CD34+ selection. Simple, practical, and reliable lymphocyte and hematopoietic progenitor cell (HPC) collection algorithms accounting for subsequent CD34+ selection have not been published. STUDY DESIGN AND METHODS: In this analysis of 15 haploidentical donors undergoing tandem lymphocyte and HPC collections, we validated one-step, practical prediction algorithms (Appendix S1, available as supporting information in the online version of this paper) that use conservative facility-specific collection efficiencies, CD34+ selection efficiency, and donor-specific peripheral counts to reliably achieve the target CD3+ and CD34+ product doses. These algorithms expand on our previously published work regarding predictive HPC collection algorithms. RESULTS: Ninety-three percent of lymphocyte and 93% of CD34+ collections achieved the final target CD3+ and CD34+ product dose when our algorithm-calculated process volumes were used. Linear regression analysis of our algorithms for CD3+, preselection CD34+, and postselection CD34+ showed statistically significant models with R2 of 0.80 (root mean square error [RMSE], 31.3), 0.72 (RMSE, 385.7), and 0.56 (RMSE, 326.0), respectively, all with p values less than 0.001. CONCLUSION: Because achievement of CD3+ or CD34+ dose targets may be critical for safety and efficacy of cell therapies, these simple, practical, and reliable prediction algorithms for lymphocyte and HPC collections should be very useful for collection facilities.


Assuntos
Algoritmos , Antígenos CD34/sangue , Doadores de Sangue , Complexo CD3/sangue , Células-Tronco Hematopoéticas/metabolismo , Leucaférese , Linfócitos T/metabolismo , Adulto , Feminino , Células-Tronco Hematopoéticas/citologia , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T/citologia
20.
Blood ; 134(18): 1498-1509, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31515250

RESUMO

Prior studies have reported high response rates with recombinant interferon-α (rIFN-α) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-α, we investigated the outcomes of pegylated-rIFN-α2a (PEG) therapy in ET and PV patients previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC)-111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET or PV who were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rates (ORRs; CR/PR) at 12 months were 69.2% (43.1% and 26.2%) in ET patients and 60% (22% and 38%) in PV patients. CR rates were higher in CALR-mutated ET patients (56.5% vs 28.0%; P = .01), compared with those in subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction was -6% (range, -84% to 47%) in patients achieving a CR vs +4% (range, -18% to 56%) in patients with PR or nonresponse (NR). Therapy was associated with a significant rate of adverse events (AEs); most were manageable, and PEG discontinuation related to AEs occurred in only 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET or PV who were previously refractory and/or intolerant of HU. This trial was registered at www.clinicaltrials.gov as #NCT01259856.


Assuntos
Antineoplásicos/uso terapêutico , Interferon-alfa/uso terapêutico , Policitemia Vera/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Trombocitemia Essencial/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Hidroxiureia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento
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