RESUMO
CC-486, the oral formulation of azacitidine (AZA), is an epigenetic modifier and DNA methyltransferase inhibitor in clinical development for treatment of hematologic malignancies. CC-486 administered for 7 days per 28-day treatment cycle was evaluated in a phase 1 dose-finding study. AZA has a short plasma half-life and DNA incorporation is S-phase-restricted; extending CC-486 exposure may increase the number of AZA-affected diseased target cells and maximize therapeutic effects. Patients with lower-risk myelodysplastic syndromes (MDS) received 300 mg CC-486 once daily for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Median patient age was 72 years (range 31-87) and 75% of patients had International Prognostic Scoring System Intermediate-1 risk MDS. Median number of CC-486 treatment cycles was 7 (range 2-24) for the 14-day dosing schedule and 6 (1-24) for the 21-day schedule. Overall response (complete or partial remission, red blood cell (RBC) or platelet transfusion independence (TI), or hematologic improvement) (International Working Group 2006) was attained by 36% of patients receiving 14-day dosing and 41% receiving 21-day dosing. RBC TI rates were similar with both dosing schedules (31% and 38%, respectively). CC-486 was generally well-tolerated. Extended dosing schedules of oral CC-486 may provide effective long-term treatment for patients with lower-risk MDS.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/farmacocinética , Azacitidina/farmacocinética , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco , Segurança , Distribuição TecidualRESUMO
Engraftment syndrome (ES) is a toxicity of autologous stem cell transplantation that occurs unexpectedly and is occasionally fatal. This syndrome, manifested as fever, rash and pulmonary deterioration which becomes evident at marrow engraftment, has been described by several centers but as yet remains enigmatic. We describe this syndrome at a single institution and note that it has accompanied the transition from the use of autologous marrow rescue to peripheral blood stem cell rescue. In this study, the occurrence of ES is related to the mononuclear cell dose at reinfusion. We found, in agreement with other reports, that patients developing ES are predominantly women undergoing therapy for solid tumors who demonstrate neutrophil engraftment at a significantly greater rate than do those patients not expressing the syndrome. We did not note a significant relationship between growth factor use (G-CSF) or amphotericin B exposure and the syndrome, as has been previously reported. The progenitor cell populations obtained with autologous marrow and peripheral blood stem cells are different. We hypothesize that the interaction of committed myeloid precursors from the stem cell product with the pulmonary vascular endothelium can be deleterious, especially under the influence of the inflammatory cytokines present at the time of engraftment.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Neoplasias/terapia , Adulto , Idoso , Dermatite/etiologia , Diarreia/etiologia , Feminino , Febre/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neutrófilos/imunologia , Síndrome , Transplante AutólogoRESUMO
BACKGROUND: Survival rates from mechanical ventilation (MV) in allogeneic bone marrow transplantation are poor, but little is known about the need for and outcomes from MV in patients who undergo autologous hematopoietic stem cell transplantation (AHSCT). STUDY OBJECTIVE: To determine the frequency of and risk factors for the use of MV in recipients of AHSCT and to identify predictors of survival in mechanically ventilated AHSCT patients. DESIGN: Retrospective, cohort analysis SETTING: Tertiary-care, university-affiliated medical center. PATIENTS: One hundred fifty-nine consecutive patients who underwent AHSCT. INTERVENTIONS: Patient surveillance and data collection. MEASUREMENTS AND RESULTS: The primary outcome measure was the need for MV, and the secondary end point was survival after MV. Of 159 patients, 17 required MV (10. 7%). Three variables were associated with the need for MV: increasing age, use of total body irradiation in the conditioning regimen, and treatment with amphotericin B. As a screening test to predict the need for MV, no risk factor had a sensitivity or specificity > 82%. Three of the 17 mechanically ventilated patients (17.6%) survived to discharge. Only the mean APACHE (acute physiology and chronic health evaluation) II score separated survivors from nonsurvivors (21.7 vs 31.4; p = 0.029). Both the duration of MV and the length of stay in the ICU were similar in survivors and nonsurvivors. CONCLUSIONS: We conclude that MV is infrequently needed following AHSCT. Although survival after MV in these patients is limited, clinical variables do not reliably allow clinicians to prospectively identify patients destined to die.
Assuntos
Cuidados Críticos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Respiração Artificial , APACHE , Adulto , Idoso , Causas de Morte , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Síndrome do Desconforto Respiratório/mortalidade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Blast expression of CD56 is frequent in patients with t(8;21)(q22;q22) acute myeloid leukemia and is associated with an inferior outcome. The expression of CD56 has rarely been reported in acute promyelocytic leukemia (APL) and has not been clinically characterized. Therefore, we examined the prognostic significance of CD56 expression in APL. PATIENTS AND METHODS: We identified all reported cases of CD56+ APL in the medical literature and collected clinical, biologic, and therapeutic details. RESULTS: Data were obtained for 12 patients with CD56+ APL (> 20% blast expression of CD56), including four cases from a single institution with a total of 42 APL patients. All of the CD56+ APL patients had documented cytogenetic presence of t(15;17), and of the nine reported isotypes, eight (89%) were S-isoform. Only six CD56+ patients (50%) attained complete remission (CR); the other six individuals died within 35 days of presentation. Of the six patients who attained a CR, three (50%) relapsed at 111, 121, and 155 weeks, whereas three remained in continuous CR at 19, 90, and 109 weeks. Comparison of the control CD56- to CD56+ APL patients demonstrated that the latter group had a significantly lower fibrinogen level (P = .007), and among patients for whom data were available, there was a higher frequency of the S-isoform (P = .006). Additionally, the CR rate (50% v 84%, P = .025) and overall median survival (5 v 232 weeks; P = .019) were significantly inferior for CD56+ APL patients. CONCLUSION: CD56+ acute promyelocytic leukemia is infrequent, seems to occur more frequently with the S-isoform subtype, and may be associated with a lower CR rate and inferior overall survival.
Assuntos
Antígeno CD56/análise , Leucemia Promielocítica Aguda/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imunofenotipagem , Leucemia Promielocítica Aguda/imunologia , Leucemia Promielocítica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Allogeneic (alloBMT) and autologous bone marrow transplantation (ABMT) have become standard approaches for the management of adults with acute myeloid leukemia (AML). The indications for transplantation remain controversial as parallel improvements in intensive chemotherapy have resulted in excellent outcomes for many patients. AlloBMT is the therapy of choice for patients who fail to respond to induction chemotherapy. For those patients in first remission (CRI), a policy of intensive postremission chemotherapy with transplantation upon relapse appears to be optimal. There are no data to support transplantation in CRI, allogeneic or autologous, for those patients with leukemia characterized by favorable cytogenetic abnormalities [ie, core-binding factor type or t(15;17)], as these patients do well with nonmyeloablative strategies. Patients with relapsed disease appear to be best served with allogeneic transplantation from a human leukocyte antigen (HLA)-matched sibling or one-antigen-mismatched family member, whereas for those patients lacking a related donor, unrelated donor alloBMT or ABMT provides similar long-term overall survival. Randomized studies for the optimal management of relapsed disease are lacking but are needed. The objective of this review is to discuss the data supporting the use of alloBMT or ABMT at various points during the course of de novo adult AML.
Assuntos
Antineoplásicos/efeitos adversos , Transplante de Medula Óssea , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Adulto , Transplante de Medula Óssea/métodos , Ensaios Clínicos como Assunto , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Estadiamento de Neoplasias , Estudos Prospectivos , Transplante Autólogo , Transplante Homólogo , Resultado do TratamentoRESUMO
The purpose of this report is to record a patient with myelodysplastic syndrome (MDS) associated acute myelogenous leukemia (AML) and leukemia cutis who had blast expression of the neural cell adhesion molecule (NCAM) and to review the world literature on prognostic implications of extramedullary myeloid cell tumors (granulocytic sarcoma, myeloblastoma, chloroma and leukemia cutis) in MDS and MDS associated AML. Case report and world literature from January 1965-January 1994 for all cases of MDS-associated extramedullary myeloid cell tumors (EMT) is reviewed, and the first patient with EMT, MDS associated AML and blast expression of NCAM is described. There have been 46 cases of MDS associated EMT previously reported. 32 cases occurred in the absence of AML. AML developed in 47% of these patients at a mean of 38 weeks from initial EMT. Of the patients not developing AML, median survival from initial EMT was 11 weeks. Nine patients received chemotherapy at the time of EMT and had a median survival of 36 weeks. The median survival for patients receiving conservative therapy for EMT was 48 weeks. Patients (n = 15) with EMT and MDS associated AML had a poor outcome regardless of therapy with a median survival of 11 weeks. Unlike other forms of isolated EMT, MDS associated EMT is not always a forerunner of AML. Premature induction therapy for MDS associated EMT does not appear to prolong survival. EMT in the setting of MDS associated AML is associated with a poor prognosis despite aggressive chemotherapy. Blast expression of NCAM may prove to be a risk factor for EMT in MDS associated AML.
Assuntos
Leucemia Mieloide Aguda/complicações , Síndromes Mielodisplásicas/complicações , Neoplasias Cutâneas/complicações , Adulto , Idoso , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Moléculas de Adesão de Célula Nervosa/biossíntese , Prognóstico , Neoplasias Cutâneas/metabolismoRESUMO
PURPOSE: To discuss the predisposing risk factor for all forms of extramedullary leukemia (EML) and to review the clinical features, prognostic significance, and treatment strategies for primary EML and leukemia cutis (LC)/granulocytic sarcomas (GS) in the setting of acute nonlymphocytic leukemia (ANLL). METHODS: A review of all reports published since 1965 related to all forms of extramedullary leukemia (LC, GS, gingival hypertrophy, and meningeal leukemia [ML]). RESULTS: Several factors, including chromosomal abnormalities [t(8;21), inv(16)], cell-surface markers (CD56, CD2, CD4, CD7), French-American-British (FAB) subtype (M2, M4, M5), blast differentiation and maturation, patient nutritional status, age, cellular immune dysfunction, high presenting leukocyte count, and decreased blast Auer rods, have been associated with a higher incidence of EML. Of 154 published cases of primary EML identified, 71 (46%) were initially misdiagnosed. The addition of immunohistochemical stains can assist in preventing such misdiagnoses and should be included in all atypical lymphoma/carcinoma cases. Only one of the patients (3%) with primary EML did not progress to ANLL in the absence of chemotherapy. In contrast, 66% of patients who received chemotherapy for the primary EML never developed ANLL. The prognostic significance of EML at presentation and medullary relapse of ANLL is uncertain. Isolated extramedullary recurrence of ANLL always heralds bone marrow relapse and should be treated with reinduction chemotherapy. Close clinical follow-up observation is necessary to insure resolution of EML. Radiation therapy is an effective local treatment for resistant or symptomatic EML. CONCLUSION: Many advances in diagnoses and treatment of EML have been made. Future investigations are needed to define the clinical significance of EML in patients with ANLL treated with modern chemotherapy or bone marrow transplantation.