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Antineoplásicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Gravidez , Feminino , Asparaginase/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Polietilenoglicóis/efeitos adversos , Antineoplásicos/uso terapêuticoRESUMO
PCR is widely used to measure minimal residual disease (MRD) in lymphoid neoplasms, but its sensitivity is limited. High Adenine/Thymine PCR and High Annealing Temperature PCR (HAT-PCR) is a modified PCR designed to minimize nonspecificity and hence increase sensitivity. It was evaluated in the laboratory and the clinic, using samples from 58 patients. Of these patients, 57 were adolescents or young adults who were participating in the Australasian Leukemia and Lymphoma Group ALL06 trial in which MRD was measured in blood principally by HAT-PCR and in marrow by conventional PCR. HAT-PCR produced significantly less nonspecificity than conventional PCR, and its limit of detection was <10-6 in 90% of patients. In 196 samples, an excellent correlation was found between blood and marrow MRD. Variable partitioning of leukemic cells between blood and marrow was observed. Measurement of MRD in blood by HAT-PCR was noninferior to measurement of MRD in marrow by conventional PCR, in terms of both detecting disease and predicting clinical outcome. At a median follow-up of 3 years and for MRD levels in blood at the end of consolidation treatment, an MRD level of >10-4 cells/L significantly predicted relapse and mortality, whereas undetectable MRD significantly predicted relapse-free survival and overall survival. HAT-PCR is a simple, quick, cheap and sensitive method for measurement of MRD, and its adoption for MRD in blood may be clinically useful.
Assuntos
Medula Óssea , Adolescente , Medula Óssea/patologia , Humanos , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Reação em Cadeia da Polimerase , Recidiva , Adulto JovemRESUMO
Pediatric regimens have improved outcomes in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL). However, results remain inferior to children with ALL. The Australasian Leukaemia and Lymphoma Group (ALLG) ALL06 study (anzctr.org.au/ACTRN12611000814976) was designed to assess whether a pediatric ALL regimen (Australian and New Zealand Children's Haematology and Oncology Group [ANZCHOG] Study 8) could be administered to patients aged 15 to 39 years in a comparable time frame to children as assessed by the proportion of patients completing induction/consolidation and commencing the next phase of therapy (protocol M or high-risk [HR] treatment) by day 94. Minimal residual disease (MRD) response stratified patients to HR treatment and transplantation. From 2012 to 2018, a total of 86 patients were enrolled; 82 were eligible. Median age was 22 years (range, 16-38 years). Induction/consolidation was equally deliverable in ALL06 as in Study 8. In ALL06, 41.5% (95% confidence interval [CI], 30.7-52.9) commenced protocol M or HR therapy by day 94 vs 39.3% in Study 8 (P = .77). Median time to protocol M/HR treatment was 96 days (interquartile range, 87.5-103 days) in ALL06 vs 98 days in Study 8 (P = .80). Induction mortality was 3.6%. With a median follow-up of 44 months (1-96 months), estimated 3-year disease-free survival was 72.8% (95% CI, 62.8-82.7), and estimated 3-year overall survival was 74.9% (95% CI, 65.3-84.5). End induction/consolidation MRD negativity rate was 58.6%. Body mass index ≥30 kg/m2 and day 79 MRD positivity were associated with poorer disease-free survival and overall survival. Pediatric therapy was safe and as deliverable in AYA patients as in children with ALL. Intolerance of pediatric ALL induction/consolidation is not a major contributor to inferior outcomes in AYA ALL.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Adolescente , Adulto , Austrália , Criança , Intervalo Livre de Doença , Humanos , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto JovemRESUMO
First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Leucemia Mieloide Aguda , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Epigênese Genética , Células Germinativas , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Linhagem , FenótipoRESUMO
Antibody-based therapy in acute myeloid leukemia (AML) has been marred by significant hematologic toxicity due to targeting of both hematopoietic stem and progenitor cells (HSPCs). Achieving greater success with therapeutic antibodies requires careful characterization of the potential target molecules on AML. One potential target is CD300f, which is an immunoregulatory molecule expressed predominantly on myeloid lineage cells. To confirm the value of CD300f as a leukemic target, we showed that CD300f antibodies bind to AML from 85% of patient samples. While one CD300f monoclonal antibody (mAb) reportedly did not bind healthy hematopoietic stem cells, transcriptomic analysis found that CD300f transcripts are expressed by healthy HSPC. Several CD300f protein isoforms exist as a result of alternative splicing. Importantly for antibody targeting, the extracellular region of CD300f can be present with or without the exon 4-encoded sequence. This results in CD300f isoforms that are differentially bound by CD300f-specific antibodies. Furthermore, binding of one mAb, DCR-2, to CD300f exposes a structural epitope recognized by a second CD300f mAb, UP-D2. Detailed analysis of publicly available transcriptomic data indicated that CD34+ HSPC expressed fewer CD300f transcripts that lacked exon 4 compared to AML with monocytic differentiation. Analysis of a small cohort of AML cells revealed that the UP-D2 conformational binding site could be induced in cells from AML patients with monocytic differentiation but not those from other AML or HSPC. This provides the opportunity to develop an antibody-based strategy to target AMLs with monocytic differentiation but not healthy CD34+ HSPCs. This would be a major step forward in developing effective anti-AML therapeutic antibodies with reduced hematologic toxicity.
Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Epitopos/imunologia , Leucemia Mieloide Aguda/tratamento farmacológico , Receptores Imunológicos/imunologia , Linhagem Celular Tumoral , Humanos , Leucemia Mieloide Aguda/imunologia , Terapia de Alvo Molecular , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Receptores Imunológicos/antagonistas & inibidoresRESUMO
To improve complete remission (CR) rates by reducing toxicity and enhancing delivery, we created a modified hyper-CVAD/MA regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone/methotrexate, cytarabine) by reducing the cytarabine dose (3 g/m2 to 2 g/m2) and number of cycles (eight to six). We conducted a phase II trial in the pre-rituximab era in the intermediate-high international prognostic index (IPI) (≥2) de novo diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL) (ACTRN12605000105640). CR rates were compared with reported IPI-stratified rates. Sixty-three patients (n = 26 PTCL; n = 37 DLBCL) were evaluated; median follow-up of 30 months. CR rates for PTCL and DLBCL patients were 46% and 49%, respectively, similar with reported CR rates with CHOP-like chemotherapy (p = .6). Of the patients, 51 (81%) experienced ≥1 unplanned hospital admission; only 41 (65%) completed six cycles. The cytarabine modifications did not prevent significant toxicity. Modified hyper-CVAD/MA resulted in similar outcomes to CHOP-like chemotherapy in aggressive lymphomas and was associated with significant toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma de Células T Periférico/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Causas de Morte , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Progressão da Doença , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Análise de Sobrevida , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêutico , Adulto JovemAssuntos
Bases de Dados Factuais , Inibidores Enzimáticos/farmacologia , Proteínas de Neoplasias , Fosfotransferases (Aceptor do Grupo Álcool) , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Inibidores Enzimáticos/química , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/enzimologiaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
Due to fewer cancer services in rural locations, rural survivors may have unique unmet needs compared to urban survivors. This study compared among rural and urban haematological cancer survivors the most common "high/very high" unmet supportive care needs and the unmet need scores for five domains (information, financial concerns, access and continuity of care, relationships and emotional health). Survivors' socio-demographics, rurality, cancer history and psychological factors associated with each unmet need domain were also explored. A total of 1511 haematological cancer survivors were recruited from five Australian state cancer registries and 1417 (1145 urban, 272 rural) allowed extraction of their residential postcode from registry records. A questionnaire that contained the Survivor Unmet Needs Survey was mailed to survivors. Dealing with feeling tired was the most common "high/very high" unmet need for rural (15.2%) and urban (15.5%) survivors. The emotional health domain had the highest mean unmet need score for rural and urban survivors. Rurality was associated with a decreased unmet emotional health domain score whereas travelling for more than 1 h to treatment was associated with increased unmet financial concerns and unmet access and continuity of care. Depression, anxiety and stress were associated with increased unmet need scores for all five domains. Unmet need domain scores generally did not differ by rurality. Travelling for more than 1 h to treatment was associated with increased unmet need scores on two domains. Telemedicine and increased financial assistance with travel and accommodation may help those travelling long distances for treatment.
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Necessidades e Demandas de Serviços de Saúde , Neoplasias Hematológicas , População Rural , Sobreviventes , População Urbana , Adolescente , Adulto , Assistência ao Convalescente/economia , Assistência ao Convalescente/psicologia , Idoso , Austrália , Continuidade da Assistência ao Paciente , Emoções , Fadiga/etiologia , Fadiga/terapia , Feminino , Acessibilidade aos Serviços de Saúde , Humanos , Comportamento de Busca de Informação , Relações Interpessoais , Masculino , Pessoa de Meia-Idade , Fatores Socioeconômicos , Sobreviventes/psicologia , Telemedicina , Viagem , Adulto JovemRESUMO
Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m2 daily for 5 days, etoposide 75 mg/m2 daily for 5 days, and idarubicin 9 mg/m2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3-internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation ( P < .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm ( P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3-internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Idarubicina/administração & dosagem , Idarubicina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Taxa de Sobrevida , Adulto JovemRESUMO
OBJECTIVE: To compare the prevalence of anxiety, depression, and stress among rural and urban support persons of haematological cancer survivors and explore factors associated with having one or more of these outcomes. METHODS: Haematological cancer survivors were identified via 1 of 5 state-based cancer registries and invited to take part in a survey. Those who agreed were asked to pass on a questionnaire package to their support person. Measures included the Depression, Anxiety, and Stress Scale, Support Persons' Unmet Need Survey, and sociodemographic questions. RESULTS: Nine-hundred and eighty-nine (66%) participating survivors had a participating support person. There were no significant differences in the proportion of urban versus rural support persons who reported elevated levels of depression (21% vs 23%), anxiety (16% vs 17%), or stress (16% vs 20%), P > .05. Odds of reporting at least 1 indicator of psychological morbidity increased by 10% to 17% for each additional high or very high unmet need and by 2% for those who had relocated from their usual place of residence for the survivor to receive treatment and was decreased by 5% to 54% for those support persons who reported that they had no chronic health conditions. CONCLUSIONS: Psychological outcomes for rural and urban support persons are similar. Those who have poor health, have had to relocate, and who have multiple unmet needs are particularly vulnerable to poor psychological outcomes. These factors should be assessed to enable early intervention for those at risk of poor outcomes.
Assuntos
Ansiedade/epidemiologia , Sobreviventes de Câncer/psicologia , Cuidadores/psicologia , Depressão/epidemiologia , População Rural , Apoio Social , População Urbana , Adulto , Idoso , Ansiedade/psicologia , Austrália/epidemiologia , Depressão/psicologia , Feminino , Neoplasias Hematológicas/etnologia , Neoplasias Hematológicas/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Grupos Raciais/psicologia , Características de Residência , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND: Most clinical allogeneic hemopoietic cell transplants (alloHCT) are now performed using reduced-intensity conditioning (RIC) instead of myeloablative conditioning (MAC); however, the biology underlying this treatment remains incompletely understood. METHODS: We investigated a murine model of major histocompatibility complex-matched multiple minor histocompatibility antigen-mismatched alloHCT using bone marrow (BM) cells and splenocytes from B6 (H-2) donor mice transplanted into BALB.B (H-2) recipients after RIC with fludarabine of 100 mg/kg per day for 5 days, cyclophosphamide of 60 mg/kg per day for 2 days, and total body irradiation (TBI). RESULTS: The lowest TBI dose capable of achieving complete donor chimerism in this mouse strain combination was 325 cGy given as a single fraction. Mice that underwent RIC had a reduced incidence and delayed onset of graft-versus-host disease (GVHD) and significantly prolonged survival compared with MAC-transplanted recipients (TBI of 850 cGy plus cyclophosphamide of 60 mg/kg per day for 2 days). Compared with syngeneic controls, RIC mice with GVHD showed evidence of BM suppression, have anemia, reduced BM cellularity, and showed profound reduction in BM B cell lymphopoiesis associated with damage to the endosteal BM niche. This was associated with an increase in BM CD8 effector T cells in RIC mice and elevated blood and BM plasma levels of T helper1 cytokines. Increasing doses of splenocytes resulted in increased incidence of GVHD in RIC mice. CONCLUSIONS: We demonstrate that the BM is a major target organ of GVHD in an informative clinically relevant RIC mouse major histocompatibility complex-matched alloHCT model by a process that seems to be driven by CD8 effector T cells.
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Doenças da Medula Óssea/prevenção & controle , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Histocompatibilidade , Complexo Principal de Histocompatibilidade , Condicionamento Pré-Transplante/métodos , Animais , Doenças da Medula Óssea/sangue , Doenças da Medula Óssea/imunologia , Linfócitos T CD8-Positivos/imunologia , Ciclofosfamida/administração & dosagem , Modelos Animais de Doenças , Esquema de Medicação , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/imunologia , Camundongos Endogâmicos BALB C , Agonistas Mieloablativos/administração & dosagem , Baço/imunologia , Fatores de Tempo , Quimeras de Transplante/imunologia , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Irradiação Corporal Total/efeitos adversosRESUMO
CD83 is a member of the Ig gene superfamily, first identified in activated lymphocytes. Since then, CD83 has become an important marker for defining activated human dendritic cells (DC). Several potential CD83 mRNA isoforms have been described, including a soluble form detected in human serum, which may have an immunosuppressive function. To further understand the biology of CD83, we examined its expression in different human immune cell types before and after activation using a panel of mouse and human anti-human CD83 mAb. The mouse anti-human CD83 mAbs, HB15a and HB15e, and the human anti-human CD83 mAb, 3C12C, were selected to examine cytoplasmic and surface CD83 expression, based on their different binding characteristics. Glycosylation of CD83, the CD83 mRNA isoforms, and soluble CD83 released differed among blood DC, monocytes, and monocyte-derived DC, and other immune cell types. A small T cell population expressing surface CD83 was identified upon T cell stimulation and during allogeneic MLR. This subpopulation appeared specifically during viral Ag challenge. We did not observe human CD83 on unstimulated human natural regulatory T cells (Treg), in contrast to reports describing expression of CD83 on mouse Treg. CD83 expression was increased on CD4+, CD8+ T, and Treg cells in association with clinical acute graft-versus-host disease in allogeneic hematopoietic cell transplant recipients. The differential expression and function of CD83 on human immune cells reveal potential new roles for this molecule as a target of therapeutic manipulation in transplantation, inflammation, and autoimmune diseases.
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Antígenos CD/metabolismo , Células Dendríticas/imunologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunoglobulinas/metabolismo , Glicoproteínas de Membrana/metabolismo , Monócitos/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Doença Aguda , Animais , Antígenos CD/genética , Antígenos Virais/imunologia , Células Cultivadas , Glicosilação , Humanos , Imunoglobulinas/genética , Ativação Linfocitária , Glicoproteínas de Membrana/genética , Camundongos , Isoformas de RNA/genética , RNA Mensageiro/genética , Transplante Homólogo , Antígeno CD83RESUMO
There are numerous transcriptional, proteomic and functional differences between monocyte-derived dendritic cells (Mo-DC) and primary blood dendritic cells (BDC). The CMRF-56 monoclonal antibody (mAb) recognizes a cell surface marker, which is upregulated on BDC following overnight culture. Given its unique ability to select a heterogeneous population of BDC, we engineered a human chimeric (h)CMRF-56 IgG4 mAb to isolate primary BDC for potential therapeutic vaccination. The ability to select multiple primary BDC subsets from patients and load them with in vitro transcribed (IVT) mRNA encoding tumor antigen might circumvent the issues limiting the efficacy of Mo-DC. After optimizing and validating the purification of hCMRF-56(+) BDC, we showed that transfection of hCMRF-56(+) BDC with mRNA resulted in efficient mRNA translation and antigen presentation by myeloid BDC subsets, while preserving superior DC functions compared to Mo-DC. Immune selected and transfected hCMRF-56(+) BDC migrated very efficiently in vitro and as effectively as cytokine matured Mo-DC in vivo. Compared to Mo-DC, hCMRF-56(+) BDC transfected with influenza matrix protein M1 displayed superior MHC peptide presentation and generated potent antigen specific CD8(+) T-cell recall responses, while Wilms tumor 1 (WT1) transfected CMRF-56(+) BDC generated effective primary autologous cytotoxic T-cell responses. The ability of the combined DC subsets within hCMRF-56(+) BDC to present mRNA delivered tumor antigens merits phase I evaluation as a reproducible generic platform for the next generation of active DC immune therapies.
RESUMO
Human plasmacytoid dendritic cells (pDCs) were considered to be a phenotypically and functionally homogeneous cell population; however, recent analyses indicate potential heterogeneity. This is of major interest, given their importance in the induction of anti-viral responses and their role in creating immunologically permissive environments for human malignancies. For this reason, we investigated the possible presence of human pDC subsets in blood and bone marrow, using unbiased cell phenotype clustering and functional studies. This defined two major functionally distinct human pDC subsets, distinguished by differential expression of CD2. The CD2(hi) and CD2(lo) pDCs represent discontinuous subsets, each with hallmark pDC functionality, including interferon-alpha production. The rarer CD2(hi) pDC subset demonstrated a significant survival advantage over CD2(lo) pDC during stress and upon exposure to glucocorticoids (GCs), which was associated with higher expression of the anti-apoptotic molecule BCL2. The differential sensitivity of these two human pDC subsets to GCs is demonstrated in vivo by a relative increase in CD2(hi) pDC in multiple myeloma patients treated with GCs. Hence, the selective apoptosis of CD2(lo) pDC during stress represents a novel mechanism for the control of innate responses.
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Antígenos CD2/metabolismo , Células Dendríticas/metabolismo , Estresse Fisiológico , Apoptose/efeitos dos fármacos , Medula Óssea/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Glucocorticoides/farmacologia , Humanos , Ligantes , Linfonodos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores Imunológicos/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Receptores Toll-Like/metabolismoRESUMO
An intensive induction regimen, consisting of idarubicin and high dose cytarabine, was assessed in 19 adult patients, median age 44 years, with newly diagnosed precursor-B acute lymphoblastic leukemia (ALL). Patients achieving a complete response (CR) were given an attenuated consolidation course. The primary endpoints were induction death rate and incidence of serious non-hematological toxicity. Grades 3-4 diarrhoea occurred in 47% of patients during induction. Two patients (11%) died during induction therapy, and 2 were withdrawn due to resistant disease or prolonged marrow hypoplasia. Fifteen patients achieved CR (79%), but levels of minimal residual disease (MRD) after induction were comparable with those previously observed using a modified pediatric protocol. Overall survival at 5 years was 36.8% while leukemia-free survival was 44.1%. An intensive AML protocol used in adults with ALL resulted in substantial toxicity and provided similar levels of cytoreduction to conventional ALL protocols, without improving long-term outcomes.
RESUMO
We compared outcomes for 2 retrospective cohorts of patients undergoing reduced-intensity conditioning (RIC) therapy transplants using haploidentical related donors and post-transplant prophylaxis against graft-versus-host disease (GVHD) with high-dose cyclophosphamide, tacrolimus, and mycophenolate. The first cohort of 13 was transplanted with bone marrow (BM) as the stem cell source, whereas the second cohort of 23 used peripheral blood stem cells (PBSCs) mobilized with granulocyte colony-stimulating factor. The BM cohort received a single 60-mg/kg dose of cyclophosphamide on day +3, whereas the PBSC cohort received 2 doses on days +3 and +4. Patients in the first cohort were slightly older and had a higher proportion of acute myeloid leukemia, but there were no differences in the distribution of Disease Risk Index scores between the 2 groups. Patients in the PBSC group received double the number of CD34(+) cells in the stem cell graft. Times to neutrophil and platelet recovery were not different between the 2 groups. Three patients, all in the PBSC group, failed to engraft but recovered with autologous hemopoiesis and survived. The 6-month cumulative incidences of acute GVHD were 55.1% for BM and 48.5% for PBSCs (P = .651), whereas 24-month cumulative rates for chronic GHVD were 28.6% for BM and 32.3% for PBSCs (P = .685). Only 2 patients, both in the BM group, died of nonrelapse causes, both of second cancers. The 2-year cumulative incidences of relapse were 43.9% for BM and 23.5% for PBSCs (P = .286). Overall survival at 2 years was significantly better for PBSC patients (P = .028), at 83.4% versus 52.7% for BM. Relapse-free and event-free survival did not differ significantly between BM and PBSC groups. In this retrospective analysis, we conclude that the use of PBSCs for haploidentical RIC transplants is a feasible strategy, with equivalent rates of acute and chronic GVHD and risk of relapse and low nonrelapse mortality compared with BM.
Assuntos
Transplante de Medula Óssea , Doença Enxerto-Hospedeiro , Hematopoese , Transplante de Células-Tronco de Sangue Periférico , Recuperação de Função Fisiológica , Doadores de Tecidos , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
High-dose cyclophosphamide given early after allogeneic hemopoietic cell transplantation has been shown to be effective prophylaxis against graft-versus-host disease (GVHD) in the setting of HLA-matched myeloablative bone marrow grafts, allowing avoidance of long-term immunosuppression with calcineurin inhibitors in some patients. Whether this approach is feasible using granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell grafts is unknown. We conducted an exploratory phase 2 trial of cyclophosphamide given at 50 mg/kg i.v. on days 3 and 4 after transplantation as sole GVHD prophylaxis in recipients of G-CSF-mobilized peripheral blood stem cell grafts from HLA-matched related or unrelated donors after reduced-intensity conditioning therapy with fludarabine, carmustine, and melphalan. Five patients, ages 52 to 67 years, with high-risk hematologic malignancies were enrolled. Four of the 5 developed severe acute GVHD of grades 3 to 4, requiring treatment with methylprednisolone and cyclosporine; 3 were steroid refractory and were given salvage therapy. One of these 4 patients died of hepatic GVHD, one died of sepsis, and 2 survived. We conclude that post-transplantation cyclophosphamide is inadequate as sole GVHD prophylaxis in the context of peripheral blood reduced-intensity conditioning transplantations from HLA-matched donors. This trial is registered at ACTRN12613001154796.
Assuntos
Ciclofosfamida/administração & dosagem , Doença Enxerto-Hospedeiro/mortalidade , Antígenos HLA , Neoplasias Hematológicas , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante , Doença Aguda , Idoso , Feminino , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
Acute myeloid leukemia (AML) blasts express high levels of interlekin-3 (IL-3) receptor-α (CD123). CSL360 is a recombinant, chimeric immunoglobulin G1 (IgG1), anti-CD123 monoclonal antibody (MoAb) that neutralizes IL-3 and demonstrates anti-leukemic activity in vitro. This phase 1 study assessed safety, pharmacokinetics and bioactivity of weekly intravenous CSL360 for 12 weeks in 40 patients with advanced AML across five dose levels (0.1-10.0 mg/kg). Other than mild infusion reactions, CSL360 was well tolerated. The maximal tolerated dose was not reached. The half-life was 4.9 days, and the area under the curve (AUC) and maximum concentration (Cmax) increased proportionally with dose. Doses ≥ 3.0 mg/kg resulted in complete saturation and down-regulation of CD123 and abolition of ex vivo proliferative responsiveness to IL-3, indicating adequate blockade of IL-3 signaling. Two patients responded, with one remaining in complete remission after 17 doses. CSL360 bound CD123 specifically, but did not induce anti-leukemic activity in most patients. While safe, MoAb blockade of CD123 function is insufficient as a therapeutic strategy.