RESUMO
BACKGROUND: Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). METHODS: We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. RESULTS: Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. CONCLUSIONS: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).
Assuntos
Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Trombose/induzido quimicamente , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas/efeitos adversos , Trombocitopenia/induzido quimicamente , Adulto JovemRESUMO
BACKGROUND: A 40-year-old man with chronic myelogenous leukemia presented multiple times over a period of 3 years with episodes of confusion, wide-based gait and falls because of recurrent hydrocephalus despite repeated therapeutic lumbar punctures. These problems occurred in the context of persistent cerebrospinal fluid (CSF) pleocytosis and leptomeningeal enhancement. Extensive diagnostic workups and therapeutic trials had failed to identify a clinically plausible cause or produce any significant improvement in the CSF and neuroimaging abnormalities. METHODS: We used high-throughput metagenomic shotgun sequencing to identify microbes in 2 CSF samples collected from the patient during his illness. These results were compared to sequence data from 1 CSF sample collected during treatment and 5 control CSF samples from other patients. RESULTS: We found sequences representing 53% and 67% of the Propionibacterium acnes genome in 2 CSF samples collected from the patient during his illness. Directed antimicrobial therapy was administered for 6 weeks with resolution of CSF and neuroimaging abnormalities. Sequencing of a sample obtained during treatment demonstrated that the P. acnes levels were decreased to background levels. After insertion of a ventriculo-peritoneal shunt, the patient returned to baseline status. CONCLUSIONS: High-throughput metagenomic shotgun sequencing revealed P. acnes as the cause of chronic meningitis that had eluded conventional attempts at diagnosis. Treatment directed at this organism resulted in cure of the infection and clinical improvement.
Assuntos
Infecções por Bactérias Gram-Positivas/líquido cefalorraquidiano , Infecções por Bactérias Gram-Positivas/microbiologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Meningites Bacterianas/líquido cefalorraquidiano , Meningites Bacterianas/microbiologia , Propionibacterium acnes/isolamento & purificação , Adulto , Antibacterianos/uso terapêutico , Ceftriaxona/uso terapêutico , Doença Crônica , Infecções por Bactérias Gram-Positivas/diagnóstico , Humanos , Hospedeiro Imunocomprometido , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Meningites Bacterianas/diagnóstico , Transplante de Células-Tronco/efeitos adversos , Transplante HomólogoRESUMO
We evaluated blood and fecal biomarkers as indicators of severity in symptomatic patients with confirmed Clostridium difficile infection (CDI). Recruitment included patients with CDI based on clinical symptoms and supporting laboratory findings. Disease severity was defined by physician's assessment and blood and fecal biomarkers were measured. Toxigenic culture done using spore enrichment and toxin B detected by tissue culture were done as confirmatory tests. Polymerase chain reaction (PCR) ribotyping was performed on each isolate. There were 98 patients recruited, with 85 (87%) confirmed cases of toxigenic CDI (21 severe, 57 moderate, and seven mild), of which 68 (80%) were also stool toxin-positive. Elevated lactoferrin (p = 0.01), increased white blood cell (WBC) count (p = 0.08), and low serum albumin (p = 0.03) were all associated with the more severe cases of CDI. Ribotype 027 infection accounted for 71% of severe cases (p < 0.01) and patients with stool toxin had significantly higher lactoferrin levels and WBC counts (p < 0.05). Our findings show that elevated fecal lactoferrin, along with increased WBC count and low serum albumin, were associated with more severe CDI. In addition, patients infected with ribotype 027 and those with stool toxin had significantly higher fecal lactoferrin and WBC counts.
Assuntos
Toxinas Bacterianas/metabolismo , Clostridioides difficile/isolamento & purificação , Infecções por Clostridium/metabolismo , Lactoferrina/metabolismo , Idoso , Análise de Variância , Toxinas Bacterianas/sangue , Biomarcadores/sangue , Biomarcadores/metabolismo , Infecções por Clostridium/sangue , Infecções por Clostridium/enzimologia , Infecções por Clostridium/microbiologia , Fezes/química , Fezes/microbiologia , Feminino , Humanos , Lactoferrina/sangue , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Ribotipagem , Albumina Sérica/metabolismoRESUMO
Cancer stem cells (CSCs) have been successfully isolated from solid tumors and are believed to be initiating cells of primary, metastatic and recurrent tumors. Imaging and therapeutic reagents targeted to CSCs have potential to detect subclinical tumors and completely eradicate the disease. Previously, we have demonstrated that Mab CC188 binds to colon cancer CD133- and CD133+ (CSCs) cells. In this study, we examined the reactivity of Mab CC188 to ovarian cancer cells including CD133+ cells and primary tumor tissues using immunofluorescence staining methods and tissue microarray technique. We also explored the feasibility of using NIR dye-labeled Mab CC188 probe to image ovarian tumors in vivo. Mab CC188 stains both CD133- and CD133+ cells of ovarian cancer. Tissue microarray analysis reveals that 75% (92/123) of ovarian cancer cases are positively stained with Mab CC188. Weak positive (±), positive (+), strong positive (++) and very strong positive (+++) stains are 14.8, 3.7, 11 and 24.4%, respectively. In contrast, Mab CC188 staining is low in normal cells and tissues. In vivo study show that significant amounts of the probe accumulates in the excretion organs in the early period postinjection. At 24 hr, the imaging probes have largely accumulates in the tumor, while the intensity of the imaging probe decreases in the liver. The tumor uptake was still evident at 120-hr postinjection. Our work suggests that Mab CC188-based imaging and therapeutic reagents are capable of detecting early stage ovarian tumors and effectively treating the tumor.
Assuntos
Anticorpos Monoclonais , Antígenos CD/análise , Glicoproteínas/análise , Células-Tronco Neoplásicas/química , Neoplasias Ovarianas/diagnóstico , Peptídeos/análise , Antígeno AC133 , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Análise Serial de TecidosRESUMO
BACKGROUND: Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant (HSCT). This pilot prospective randomized clinical trial compares valganciclovir (VGV) to ganciclovir (GCV) as pre-emptive therapy for CMV viremia in the post-allogeneic HSCT population. METHODS: Patients undergoing allogeneic HSCT who were at risk for CMV viremia were monitored post HSCT by weekly quantitative whole blood polymerase chain reaction. Pre-emptive therapy was delayed until the viral load (VL) was >10,000 copies/mL once, or >5000 copies/mL twice. Patients were randomized to either GCV 5 mg/kg twice a day (b.i.d.) for 7 days followed by daily GCV 5 mg/kg for up to 21 days, or VGV 900 mg b.i.d. for 7 days followed by 900 mg daily for up to 21 days. The primary endpoint was clearance of viremia (VL <5000 copies/mL) within 28 days of initiation of therapy. RESULT: In total, 37 patients were enrolled; 19 patients received treatment with VGV and 18 patients received treatment with GCV. The VGV was not inferior in efficacy to GCV as pre-emptive therapy, with rates of viral clearance at 28 days of 89.5% and 83%, respectively (P-value for non-inferiority = 0.030). Toxicities were similar between the 2 arms. No patients developed CMV disease. CONCLUSIONS: In this trial, the rates of clearance of viremia appear to be similar with VGV and GCV.
Assuntos
Antivirais/uso terapêutico , Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/análogos & derivados , Ganciclovir/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Viremia/prevenção & controle , Administração Oral , Adolescente , Adulto , Antivirais/administração & dosagem , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/virologia , Relação Dose-Resposta a Droga , Feminino , Ganciclovir/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Reação em Cadeia da Polimerase , Estudos Prospectivos , Transplante Homólogo , Valganciclovir , Carga Viral/efeitos dos fármacos , Viremia/virologia , Adulto JovemRESUMO
Graft-versus-host disease (GvHD) is the major limiting toxicity of allogeneic bone marrow transplantation. T cells are important mediators of GvHD, but the molecular mechanisms that they use to induce GvHD are controversial. Three effector pathways have been described for cytotoxic T lymphocytes: one requires perforin and granzymes, the second Fas (APO-1; CD95) and its ligand. Thirdly, secreted molecules (e.g., TNF-alpha, gamma-IFN) can also mediate cytotoxicity. Together, these mechanisms appear to account for virtually all cytotoxicity induced by activated CTL in standard in vitro lytic assays. Using transplants across histocompatibility barriers, we were able to analyze the contributions of these effector molecules to cell-mediated cytotoxicity in vivo in a GvHD model. We found that Fas ligand is an important independent mediator of class II-restricted acute murine GvHD, while perforin/granzyme-dependent mechanisms have only a minor role in that compartment. In contrast, perforin/ granzyme-dependent mechanisms are required for class I-restricted acute murine GvHD, while Fas ligand is not. The perforin/granzyme pathway may therefore represent a novel target for anti-GvHD drug design. In support of this approach, we provide additional data suggesting that specific perforin/granzyme inhibitors should not adversely affect hematopoietic recovery after transplantation.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Linfócitos T CD8-Positivos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Glicoproteínas de Membrana/fisiologia , Serina Endopeptidases/fisiologia , Animais , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/transplante , Ciclofosfamida/farmacologia , Proteína Ligante Fas , Fator Estimulador de Colônias de Granulócitos/farmacologia , Granzimas , Hematopoese/imunologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Perforina , Proteínas Citotóxicas Formadoras de Poros , Serina Endopeptidases/metabolismo , Taxa de Sobrevida , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/metabolismoRESUMO
The purpose of this study was to analyze the prognostic significance of early lymphocyte recovery after autologous SCT (ASCT) in the setting of routine post transplant administration of GM-CSF in patients with non-Hodgkin's lymphoma (NHL). This is a single institution retrospective comparative outcome analysis in a cohort of 268 relapsed chemosensitive NHL patients divided into two groups (early and late lymphocyte recovery) based on absolute lymphocyte counts (ALC) obtained on post transplant day +15 (ALC > or = 500, n=151 (56%) and ALC < 500, n=117 (44%)). Patient's characteristics were well-balanced between the two groups with regard to age, sex, preparative regimen, prior therapy, time from diagnosis to transplant and number of CD34+ cells infused. Post transplant complications were comparable in the two groups. Late lymphocyte recovery (ALC < 500 on day +15) was independently associated with a delay in platelet recovery (29 vs 21 days, P=0.0003) in patients who have not received pre-transplant rituximab. With a median follow-up of 22 months, no associations between early lymphocyte recovery and improvement of disease-free and overall survival were observed for either low- or intermediate-grade NHL. In conclusion, in this large single-centered retrospective analysis, where patients received routine post transplant GM-CSF, early lymphocyte recovery was not associated with favorable outcomes.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Contagem de Linfócitos , Linfócitos/imunologia , Linfoma não Hodgkin/terapia , Transfusão de Plaquetas , Transplante de Células-Tronco , Adulto , Idoso , Antígenos CD/sangue , Antígenos CD34/sangue , Feminino , Humanos , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutropenia/epidemiologia , Prognóstico , Estudos Retrospectivos , Transplante de Células-Tronco/efeitos adversos , Transplante Autólogo , Resultado do TratamentoRESUMO
Donor-lymphocyte infusion (DLI) for relapse following haploidentical hematopoietic cell transplantation (haploHCT) with post-transplant cyclophosphamide (PTCy) has been described in recipients of bone marrow grafts, but not recipients of G-CSF mobilized peripheral blood (PB) grafts. We retrospectively identified patients who underwent DLI following PB-haploHCT with PTCy for relapse, or loss of chimerism (LOC). Twelve patients (57%) received DLI for hematologic relapse/persistent disease, seven (33%) for extramedullary relapse and two (10%) for LOC. Sixteen (76%) received chemotherapy prior to DLI, which did not correlate with response. The most common first dose was 1 × 106 CD3+ cells/kg. Two patients developed grade I aGvHD post DLI, one had grade II and two had grade III. One developed mild skin cGvHD 1361 days post DLI. Pre-DLI aGvHD predicted post-DLI aGvHD (P=0.025). Six patients achieved CR after DLI for overt relapse, one achieved full donor chimerism after LOC. Patients with LOC or EM relapse had superior relapse-free survival following DLI (P=0.029). DLI following PB-haploHCT with PTCy is a viable salvage therapy for overt relapse or LOC without a substantial increase in GvHD, and donor lymphocytes may be collected simultaneously with graft collection to facilitate availability in patients at high risk of relapse.
Assuntos
Ciclofosfamida/uso terapêutico , Transfusão de Linfócitos , Transplante de Células-Tronco de Sangue Periférico/métodos , Terapia de Salvação/métodos , Idoso , Intervalo Livre de Doença , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/terapia , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Doadores de Tecidos , Transplante Haploidêntico , Resultado do TratamentoRESUMO
Traditional response criteria in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are based on bone marrow morphology and may not accurately reflect clonal tumor burden in patients treated with non-cytotoxic chemotherapy. We used next-generation sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced (exome or 285 gene panel). We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden (that is, mutations) for at least 1 year without disease progression. Using an ultrasensitive sequencing approach, we detected extremely rare mutations (equivalent to 1 heterozygous mutant cell in 2000 non-mutant cells) months to years before their expansion at disease relapse. While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone occurs at relapse or progression. Here we demonstrate that sequencing of serial samples provides an alternative measure of tumor burden in MDS or AML patients and augments traditional response criteria that rely on bone marrow blast percentage.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Evolução Clonal/genética , Epigênese Genética/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Exoma , Feminino , Genes p53 , Sequenciamento de Nucleotídeos em Larga Escala , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/diagnóstico , Polimorfismo de Nucleotídeo Único , Indução de Remissão , Resultado do Tratamento , Carga TumoralRESUMO
Quantitative polymerase chain reaction (QPCR) for cytomegalovirus (CMV) is emerging as the preferred screening method for detection of CMV viremia in patients following allogeneic bone marrow and peripheral blood stem cell transplant. However, there are currently no universally accepted QPCR treatment thresholds at which to start pre-emptive therapy. We report here results of a pre-emptive therapy strategy using ganciclovir (GCV) 5 mg/kg initiated once daily (ODG) delayed till a threshold CMV load of > or =10 000 copies/ml whole blood in clinically stable patients. Sixty-nine at risk patients underwent allogeneic stem cell transplant. 48/69 (70%) patients had an initial episode of CMV viremia. 5/48 (10%) cleared viremia without requiring treatment. 28/43 (65%) patients requiring treatment initiated treatment with ODG. 17/28 (61%) patients successfully cleared CMV viremia on ODG, 10/28 (36%) patients required dose escalation to twice daily GCV for increasing viral loads. There were two cases of CMV disease (colitis) and no deaths due to CMV disease in patients initiating treatment with ODG. We conclude delaying pre-emptive therapy with ODG until whole blood QPCR> or =10 000 copies/ml is a safe and effective strategy for CMV viremia after allogeneic stem cell transplant in clinically stable patients.
Assuntos
Antivirais/administração & dosagem , Transplante de Medula Óssea , Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus , Ganciclovir/administração & dosagem , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco de Sangue Periférico , Adulto , Idoso , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/etiologia , DNA Viral/sangue , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Transplante Homólogo , Carga Viral/métodosRESUMO
Patients with hematologic malignancies and hematopoietic stem cell transplant (HSCT) recipients are at high risk for bacterial bloodstream infections (BSI) owing to resistant organisms. Data describing the outcomes of vancomycin-resistant enterococcal (VRE) BSI in this patient population are limited. We performed a retrospective cohort study of all cases of VRE BSI that occurred between February 1996 and December 2002 on the Leukemia/HSCT unit at Barnes-Jewish Hospital. There were 68 episodes of VRE BSI in 60 patients with acute (53%) or chronic (8%) leukemia, non-Hodgkin's lymphoma (22%) or other malignant hematologic disorders (17%). A total of 13, 32 and 32% were recipients of autologous, related and matched-unrelated transplants, respectively. Forty-two of allograft recipients had active acute graft-versus-host disease (GVHD) and 32% chronic GVHD. Only 57% were neutropenic, 52% had refractory/relapsed malignancy and 60% had end organ dysfunction with a median APACHE II score of 17. Median survival after VRE BSI was 19 days. Pneumonia, receipt of anti-fungal drugs and low APACHE II score at the time of the VRE BSI remained significant risk factors for death on multivariable analysis. Our analysis suggests that in patients with hematological malignancies or HSCT, VRE may not have the behavior of a virulent pathogen. VRE BSI may simply be a marker of these patients' already existing critical medical condition.
Assuntos
Enterococcus , Infecções por Bactérias Gram-Positivas/mortalidade , Neoplasias Hematológicas/mortalidade , Transplante de Células-Tronco Hematopoéticas , Resistência a Vancomicina , APACHE , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/etiologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Autólogo , Transplante HomólogoRESUMO
The mammaglobin gene encodes a novel, breast cancer-associated glycoprotein. In this study, we have evaluated the frequency with which mammaglobin expression can be detected in primary and metastatic breast tumors and in breast tumor cells present in the peripheral circulation. Of 100 primary human breast tumors examined, 81 were strongly immunopositive for mammaglobin protein. Staining was independent of tumor grade and histological type. Ten of 11 lymph nodes from patients with metastatic breast cancer contained detectable mammaglobin mRNA, whereas mammaglobin expression in uninvolved lymph nodes was undetectable. Using a nested reverse transcription-PCR assay, mammaglobin mRNA was also detected in 9 of 15 products (60%) used for autologous stem cell transplant. These results suggest that larger clinical studies are warranted to investigate the full clinical utility of mammaglobin as a tool for breast cancer patient management.
Assuntos
Neoplasias da Mama/patologia , Mama/metabolismo , Proteínas de Neoplasias/genética , Transcrição Gênica , Uteroglobina/genética , Sequência de Aminoácidos , Mama/citologia , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática , Mamoglobina A , Dados de Sequência Molecular , Metástase Neoplásica , Proteínas de Neoplasias/análise , Neoplasias Primárias Desconhecidas/genética , Neoplasias Primárias Desconhecidas/metabolismo , Neoplasias Primárias Desconhecidas/patologia , Fragmentos de Peptídeos/imunologia , Uteroglobina/análiseRESUMO
Post-transplant cyclophosphamide (PT-Cy) is the backbone of GvHD prophylaxis following haploidentical hematopoietic cell transplantation (haplo-HCT). PT-Cy has also been used in matched related (MRD) and unrelated (MUD) settings. It is not known whether outcomes are similar between haplo-HCT and MRD/MUD HCT when PT-Cy is used. We performed a retrospective analysis of 83 patients with AML who underwent HCT (using PT-Cy-based GvHD prophylaxis) from MRD, MUD or haploidentical donors. The groups were similar in baseline characteristics with the exception of older age in the MRD/MUD group (P=0.012). In multivariate analysis, the effect of donor type (MRD/MUD vs haploidentical) on transplant outcomes was not significant in any of the models except for faster neutrophil recovery after MRD/MUD transplants (hazard ratio: 2.21; 95% confidence interval: 1.31-3.72, P=0.002). In conclusion, we showed similar outcomes in MRD/MUD vs haploidentical HCT (except slower count recovery following haplo-HCT) when PT-Cy is used for GvHD prophylaxis. Although slower count recovery following haplo-HCT (compared with MRD/MUD transplants without PT-Cy) has been attributed to using PT-Cy, our results suggest that HLA disparity is the primary cause of this difference. Furthermore, our analysis supports PT-Cy as a viable option for GvHD prophylaxis after MRD/MUD transplants.
Assuntos
Ciclofosfamida/administração & dosagem , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Adolescente , Adulto , Idoso , Doadores de Sangue , Feminino , Sobrevivência de Enxerto , Haplótipos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Histocompatibilidade , Humanos , Leucemia Mieloide Aguda/complicações , Masculino , Pessoa de Meia-Idade , Pré-Medicação , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: To determine the risks of graft-versus-host disease (GVHD) and transplant-related mortality after allogeneic peripheral-blood stem-cell (PBSC) transplantation. PATIENTS AND METHODS: Between December 1994 and July 1996, 50 consecutive patients with high-risk hematologic malignancies in first remission or relapse received high-dose therapy followed by transplantation of granulocyte colony-stimulating factor-mobilized, allogeneic PBSCs collected from HLA-identical siblings. GVHD prophylaxis included cyclosporine and corticosteroids. RESULTS: As of April 1, 1998, 18 patients (36%+/-13%) survived with a median follow-up period of 767 days (range, 602 to 1,127 days). The actuarial probability of grades 2-4 acute GVHD was 0.37+/-0.14 (95% confidence interval). Of 36 assessable patients, 26 (72%+/-15%) developed chronic GVHD. The actuarial probability of chronic GVHD 2 years after transplantation was 0.87+/-0.15. Of 14 progression-free survivors, 11 (79%+/-22%) have active, chronic GVHD. All 11 patients require ongoing immunosuppression, and nearly two thirds have extensive disease. Thirteen patients died as a result of transplant-related mortality (26%+/-12%), six (12%) before and seven (14%) after day +100. CONCLUSION: We observed a high risk of chronic GVHD after allogeneic PBSC transplantation, which compromised the performance status of most long-term survivors and resulted in a relatively high risk of late transplant-related mortality. Approximately 75% of transplant-related deaths were associated with GVHD; thus, reduction in transplant-related mortality after allogeneic PBSC transplantation will require more effective strategies for the prophylaxis and/or treatment of GVHD.
Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Leucemia/terapia , Adolescente , Adulto , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Leucemia/sangue , Estudos Longitudinais , Pessoa de Meia-Idade , Risco , Análise de Sobrevida , Transplante HomólogoRESUMO
PURPOSE: To determine the number of CD34+ cells associated with a high probability of rapid engraftment after allogeneic peripheral-blood stem-cell (PBSC) transplant, and to examine the relationship between certain donor characteristics and the effectiveness of PBSC mobilization. PATIENTS AND METHODS: Between December 1994 and July 1996, we treated 47 patients who had resistant hematologic neoplasms with myeloablative therapy followed by transplantation of allogeneic PBSC collected from histocompatible siblings after mobilization with granulocyte colony-stimulating factor (G-CSF). Expression of CD34 was determined by flow cytometry. RESULTS: Engraftment was rapid and similar to that observed following autologous PBSC transplant, with an absolute neutrophil count (ANC) greater than 500/microL and platelet count greater than 20,000/microL on median days +9 and +11, respectively. The pace of hematologic recovery correlated with the number of hematopoietic progenitors transplanted, so that patients who received greater than 5 x 10(6) CD34+ cells/kg recipient weight had a 95% likelihood of neutrophil and platelet recovery by day +15. Baseline (precytokine) CD34+ cells per milliliter of donor peripheral blood and total G-CSF dose (donor weight x 10 micrograms/kg) correlated with the number of CD34+ cells collected (R2 = .24 and P = .0009, and R2 = .24 and P < .0001, respectively). Donor age and sex did not effect mobilization. CONCLUSION: Following allogeneic PBSC transplant, patients who received greater than 5 x 10(6) CD34+ cells/ kg recipient weight had a high probability of rapid engraftment. Donors with low baseline levels of circulating progenitors (< 2,000 CD34+ cells/mL blood) and those who received lower total doses of G-CSF were less likely to be effectively mobilized. For donors with low baseline CD34+ counts, higher doses of G-CSF might improve mobilization. Baseline CD34+ counts and total G-CSF dose accounted for less than half of the variation in CD34+ cells collected, which indicates that other, as yet unidentified, factors play an important role in determining the effectiveness of mobilization.
Assuntos
Antígenos CD34/análise , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Adolescente , Adulto , Coleta de Amostras Sanguíneas , Separação Celular , Criança , Feminino , Hematopoese/imunologia , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Transplante HomólogoRESUMO
PURPOSE: To evaluate the safety and hematopoietic activity of daniplestim administered concurrently with granulocyte colony-stimulating factor (G-CSF) for peripheral-blood stem-cell (PBSC) mobilization. PATIENTS AND METHODS: In the initial dose-escalation phase, 25 patients with adenocarcinoma of the breast (AB; 13 patients) or lymphoma (12 patients) were given daniplestim at doses ranging from 0.1 to 3.75 microgram/kg/d plus G-CSF 10 microgram/kg/d. In the randomized phase, 52 patients with AB (27 patients) or lymphoma (25 patients) were randomized within disease categories to the daniplestim dose chosen in the dose-escalation phase plus G-CSF 10 microgram/kg/d (D+G) or placebo plus G-CSF 10 microgram/kg/d (P+G) for up to 7 days. RESULTS: A daniplestim dose of 2. 5 microg/kg/d was chosen for further study because it was hematopoietically active and had an acceptable side-effect profile. In the randomized phase, in patients with AB, D+G was associated with a higher probability (P =.0696) of collecting >/= 2.5 x 10(6) CD34(+) cells/kg and significantly higher circulating CD34(+) cell counts (P =.0498) on days 6 through 9 after the initiation of dosing. The target level was more likely to be reached with additional leukaphereses in the patients given D+G. Patients given P+G did not benefit from additional leukaphereses beyond the first procedure. The type of mobilization did show a trend toward a shorter duration of neutropenia in the D+G group. The adverse events with D+G consisted largely of mild to moderate flu-like symptoms, including headache and fever, and occurred more frequently than with P+G. CONCLUSION: Daniplestim administered at 2.5 microgram/kg/d is tolerable and active when combined with G-CSF, and the combination may prove more effective than G-CSF alone in promoting the collection of adequate numbers of CD34(+) cells for PBSC infusion in patients with AB.
Assuntos
Adenocarcinoma/terapia , Neoplasias da Mama/terapia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Linfoma/terapia , Peptídeos/administração & dosagem , Adenocarcinoma/imunologia , Adulto , Antígenos CD34 , Antineoplásicos/uso terapêutico , Neoplasias da Mama/imunologia , Método Duplo-Cego , Esquema de Medicação , Transplante de Células-Tronco Hematopoéticas , Humanos , Interleucina-3 , Contagem de Linfócitos , Linfoma/imunologia , Fragmentos de PeptídeosRESUMO
PURPOSE: Although high-dose chemotherapy supported by autologous peripheral-blood progenitor-cell (PBPC) transplantation improves response rates and survival for patients with multiple myeloma, all patients eventually develop progressive disease after transplantation. It has been hypothesized that depletion of malignant plasma cells from autografts may improve outcome by reducing infused cells contributing to relapse. PATIENTS AND METHODS: A randomized phase III study using the CEPRATE SC System (Cellpro, Bothell, WA) to enrich CD34(+) autograft cells and passively purge malignant plasma cells was completed in 190 myeloma patients randomized to receive an autograft of CD34-selected or unselected PBPCs. RESULTS: After CD34 selection, tumor burden was reduced by 1.6 to 6.0 logs (median, 3.1), with 54% of CD34-enriched products having no detectable tumor. Median time to count recovery, number of transfusions, transplantation-related mortality, and days in hospital were equivalent between the two transplantation arms. With a median follow-up of 37 months, 33 patients (36%) in the selected and 34 patients (35%) in the unselected arm had died (P =.784). Median overall survival in the selected arm was reached at 50 months and is not reached at this time in the unselected arm (P =.78). Median disease-free survival was 100 versus 104 weeks (P =.82), with 67% of patients in the selected arm and 66% of patients in the unselected arm relapsing. CONCLUSION: This phase III trial demonstrates that although CD34 selection significantly reduces myeloma cell contamination in PBPC collections, no improvement in disease-free or overall survival was achieved.
Assuntos
Antígenos CD34/análise , Purging da Medula Óssea/métodos , Mieloma Múltiplo/terapia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/mortalidade , Células Neoplásicas Circulantes/imunologia , Reação em Cadeia da Polimerase , Modelos de Riscos Proporcionais , Taxa de SobrevidaRESUMO
PURPOSE: To evaluate the disease-free survival (DFS) and overall survival (OS), prognostic factors, and treatment-related mortality of women with stage IIIB inflammatory breast cancer (IBC) treated with combined modality therapy (CMT) and high-dose chemotherapy (HDCT) with autologous stem-cell transplantation. PATIENTS AND METHODS: Between 1989 and 1997, 47 consecutive patients with stage IIIB IBC were treated with CMT and HDCT and were the subject of this retrospective analysis. Chemotherapy was administered to all patients before and/or after definitive surgery. Neoadjuvant and adjuvant chemotherapy was administered to 33 and 34 patients, respectively, and 20 patients received both. All patients received HDCT with autologous stem-cell transplantation, and 41 patients received locoregional radiation therapy. Tamoxifen was prescribed to patients with estrogen receptor (ER)-positive cancer. RESULTS: The mean duration of follow-up from diagnosis was 30 months (range, 6 to 91 months) and from HDCT was 22 months (range, 0.5 to 82 months). At 30 months, the Kaplan-Meier estimates of DFS and OS from diagnosis were 57.7% and 59.1%, respectively. At 4 years, the Kaplan-Meier estimates of DFS and OS from diagnosis were 51.3% and 51.7%, respectively. In a multivariate analysis, the only factors associated with better survival were favorable response to neoadjuvant chemotherapy (P =.04) and receipt of tamoxifen (P =.06); however, the benefit of tamoxifen was only demonstrated in patients with ER-positive breast cancer. At last follow-up, 28 patients (59. 6%) were alive and disease-free. Seventeen patients (36.2%) developed recurrent breast cancer. Seventeen patients died: 15 from disease recurrence and two (4.2%) from treatment-related mortality due to HDCT. CONCLUSION: In this analysis, the early results of treatment with CMT and HDCT compare favorably with other series of patients with stage IIIB IBC treated with CMT alone. These outcomes must be confirmed with longer follow-up and controlled studies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/terapia , Transplante de Células-Tronco Hematopoéticas , Adulto , Análise de Variância , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Terapia Combinada/métodos , Intervalo Livre de Doença , Feminino , Humanos , Mastectomia Radical Modificada , Pessoa de Meia-Idade , Terapia Neoadjuvante , Oregon/epidemiologia , Prognóstico , Modelos de Riscos Proporcionais , Radioterapia , Estudos Retrospectivos , Análise de Sobrevida , Taxa de Sobrevida , Tamoxifeno/uso terapêutico , Texas/epidemiologia , Resultado do Tratamento , Washington/epidemiologiaRESUMO
Interleukin 6 (IL-6) is a major growth factor for myeloma cells and retinoids have been shown to inhibit expression of the interleukin 6 receptor (IL-6R). We performed a pilot study to assess the efficacy and tolerability of 13cis retinoic acid (13cRA) and dexamethasone (Dex), when added to interferon alpha (IFNalpha) as maintenance therapy post autologous stem cell transplantation. Between 90 and 120 days post stem cell transplantation, 33 patients were started on 13cRA 1 mg/kg p.o. daily for 14 days and Dex 40 mg p.o daily for 5 days every month. 13cRA was dose escalated by 0.5 mg/kg/month to 2 mg/kg. Seventeen patients had a persistent paraprotein post transplant. Overall, a response to therapy was observed in 11/17 (64%), with a complete response in 4/17 (23.5%) and a partial response (>/=50% paraprotein decline) in 7/17 (41%). With a median follow-up of 34.8 months, 22/33 (66%) demonstrated disease progression and 11/33 (33%) died. The median progression-free survival from diagnosis was 34.7 months. Although a decline in paraprotein was frequently observed on triple therapy, many patients discontinued therapy due to the side-effects of the IFNalpha. Future trials should be designed using 13cRA and Dex alone.
Assuntos
Dexametasona/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Interferon-alfa/administração & dosagem , Isotretinoína/administração & dosagem , Mieloma Múltiplo/terapia , Adulto , Idoso , Quimioterapia Combinada , Feminino , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Projetos Piloto , Receptores de Interleucina-6/sangue , Transplante AutólogoRESUMO
Bone marrow transplantation (BMT) benefits nonmalignant diseases but is limited by regimen-related toxicity, graft-versus-host disease (GVHD), donor availability, and graft rejection (GR). To overcome some of these barriers, we developed a new conditioning strategy for these patients. In total, 16 patients received Campath-1H (33/48 mg; days -21 to -19), fludarabine (150 mg/m(2); days -8 to -4), melphalan (140/70 mg/m(2); day -3), and transplant using related/unrelated stem cells. GVHD prophylaxis included cyclosporine/methylprednisolone for cord cells. Other recipients also received methotrexate. Risk factors for GR included multiple transfusions (6), low stem cell numbers (1), and immunologic/metabolic disorders (3). Donor engraftment was present in 14/16 recipients. Neutrophils (ANC>0.5 x 10(9)/l) and platelets (>50 x 10(9)/l) engrafted at a median of 13 and 24 days. Two patients died of Pseudomonas sepsis prior to engraftment, one of CMV disease, and another of intracranial hemorrhage. With median follow-up of 281 days (78-907), 12/16 are stable/improved, or cured. Acute GVHD was absent (n=10) or mild and transient (grade1-2 skin) (n=4). There was no chronic GVHD. Toxicities were predominantly early infections within 100 days, and correlated with lymphopenia (CD4+ T and B cells). Stable engraftment and low incidence of significant GVHD, irrespective of age or stem cell source, make this reduced-intensity regimen attractive for nonmalignant disorders.