RESUMEN
We analyzed the late outcomes of 429 long-term survivors post allogeneic hematopoietic SCT (allo-HSCT) who received transplant in our center between 1981 and 2002, and were free of their primary disease for > or =2 years after allo-HSCT. Late recurrent primary malignancy was found in 58 (13.5%) patients and was the primary cause of late death. A total of 37 (8.6%) patients died of non-relapse causes at a median of 5.5 years (range, 2-15.6 years) post allo-HSCT. The major non-relapse causes of death were chronic GVHD (cGVHD), secondary malignancy and infection. The probabilities of OS and EFS were 85% (95% cumulative incidence (CI) (81-89%)) and 79% (95% CI (74-83%)) at 10 years, respectively. Long-term allo-HSCT survivors were evaluated for late complications (median follow-up, 8.6 years (range, 2.3-22.8 years)). cGVHD was diagnosed in 196 (53.1%) survivors. The endocrine and metabolic complications were hypogonadism in 134 (36.3%) patients, osteopenia/osteoporosis in 90 (24.4%), dyslipidemia in 33 (8.9%), hypothyroidism in 28 (7.6%) and diabetes in 28 (7.6%). Hypertension was diagnosed in 79 (21.4%), renal impairment in 70 (19.0%), depression in 40 (10.8%) and sexual dysfunction in 33 (8.9%) survivors. We conclude that in patients who receive allo-HSCT as treatment for hematological malignancy and who are free of their original disease 2 years post transplant, mortality is low and the probability of durable remission is high. Lifelong surveillance is recommended.
Asunto(s)
Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Adolescente , Adulto , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Neoplasias Hematológicas/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Infecciones/etiología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/mortalidad , Pronóstico , Recurrencia , Sobrevivientes , Acondicionamiento Pretrasplante , Trasplante Autólogo , Trasplante Homólogo/efectos adversos , Resultado del TratamientoRESUMEN
Outcome is poor with conventional therapy for relapsed transformed non-Hodgkin's lymphoma (NHL). Autologous SCT has been successfully employed; however the impact of allogeneic SCT has not been well defined. We therefore studied 40 consecutive patients who received allogeneic SCT for relapsed composite and transformed NHL (25 transformed, 8 composite (same site) and 7 discordant (different sites)) with related (n=25) and unrelated donors (n=15) to evaluate long-term outcome. Conditioning was myeloablative in the majority (39 of 40). Of 40 patients, 11 survive with median follow-up of 25 months. Death occurred in similar proportions due to relapsed NHL (n=14) or treatment-related complications (transplant-related mortality, TRM; n=15). The cumulative incidence of TRM was 36% at 3 years and disease relapse was 42% at 5 years. Probability of 2- and 5-year event-free survival is 36 and 23% with overall survival 39 and 23%. Performance of SCT within 1 year of NHL diagnosis predicted improved outcome. Relapse and TRM remain significant problems in this setting, indicating the need for strategies whereby patients at high risk of transformation should be selected for early SCT, ideally before their actual transformation.
Asunto(s)
Donadores Vivos , Linfoma no Hodgkin/terapia , Trasplante de Células Madre/métodos , Adulto , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Tasa de Supervivencia , Acondicionamiento Pretrasplante/métodos , Resultado del TratamientoRESUMEN
Administration of alkylating agents (Alk), topoisomerase II inhibitors (Topo II) and radiotherapy (RT) can result in therapy-related myelodysplastic syndrome or acute myelogenous leukaemia (t-MDS/t-AML), the optimal treatment for which is allo-SCT. A retrospective review was performed of 24 patients who underwent related- or unrelated-donor SCT for t-MDS/t-AML at our institution. Eight patients remain alive and in continuous remission (median follow-up 54 months (range, 12-161)) with estimated 5-year EFS being 30% (95% confidence intervals 16-58%). Corresponding actuarial risks of relapse and non-relapse mortality (NRM) are 39% (19-60%) and 30% (13-50%), respectively. EFS was 40% in Alk/RT-related t-MDS/t-AML and 11% in Topo II-related t-MDS/t-AML (P=0.05), with an increased risk of relapse in the latter (56 vs 29%, respectively (P=0.05)). In multivariate analysis, development of acute GVHD (P=0.009) and Topo II-related t-MDS/t-AML (P=0.018) were associated with inferior EFS. Patients with acute GVHD had an increased risk of NRM (P=0.03) whereas risk of relapse was higher for patients of advanced age (P=0.046) and for patients who underwent bone marrow (vs blood) SCT (P=0.032). Allo-SCT can result in long-term survival for individuals with t-MDS/t-AML although outcome in Topo II-related t-MDS/t-AML patients remains suboptimal.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/efectos adversos , Síndromes Mielodisplásicos/terapia , Neoplasias Primarias Secundarias/terapia , Adulto , Alquilantes/efectos adversos , Inhibidores Enzimáticos/efectos adversos , Femenino , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/mortalidad , Pronóstico , Radioterapia/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Inhibidores de Topoisomerasa II , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Curative intent chemotherapy for acute myelogenous leukemia (AML) leads to prolonged severe neutropenia, during which patients are highly susceptible to infection. Traditionally these high-risk patients were treated as inpatients. Our center recently implemented a selective ambulatory management policy for AML patients undergoing chemotherapy. MATERIALS AND METHODS: A retrospective analysis was conducted to assess the occurrence of septicemia in AML patients treated over a 5 years period with curative intent chemotherapy. This review encompasses a change in policy from primarily inpatient care to selective outpatient management coupled with prophylactic antibiotic therapy. RESULTS: A total of 294 patients, receiving 623 cycles of chemotherapy were identified. A significant decrease in septicemia was observed from the inpatient to outpatient cohort (22% to 13% P < 0.05), which correlated with the shift towards outpatient treatment of consolidation cycles. A shift from Gram-negative to Gram-positive organisms as the cause of septicemia was also detected in the outpatient cohort, likely due to the introduction of ciprofloxacin prophylaxis. No significant emerging resistance and no septicemia-related mortality were noted in the outpatient cohort. CONCLUSION: The observed decrease in the incidence of septicemia in the ambulatory cohort adds supportive evidence to the feasibility of selective outpatient management of AML patients with respect to infectious complications.
Asunto(s)
Atención Ambulatoria , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Sepsis/epidemiología , Adolescente , Adulto , Anciano , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Neutropenia/complicaciones , Neutropenia/etiología , Estudios Retrospectivos , Sepsis/etiología , Sepsis/microbiologíaRESUMEN
BACKGROUND: Controversy exists regarding the role of high-dose therapy followed by stem-cell transplant (SCT) in the treatment of T-cell lymphoblastic lymphoma (T-LBL). We conducted an intention-to-treat analysis of the strategy of SCT as definitive treatment of T-LBL. PATIENTS AND METHODS: From July 1987 to March 2005, 34 adults with T-LBL were diagnosed and treated in British Columbia. Treatment, before planned SCT, consisted of a non-Hodgkin's lymphoma (NHL)/acute lymphoblastic leukemia hybrid chemotherapy protocol (28 patients) or a standard NHL chemotherapy regimen (six patients). RESULTS: Median follow-up of the 23 surviving patients is 51 months (range 13-142 months). Twenty-nine proceeded to SCT (four allogeneic, 25 autologous). For all 34 patients, 4-year overall survival (OS) and event-free survival (EFS) are 72% and 68%, respectively. For patients proceeding to SCT, the 4-year OS and EFS are 79% and 73%, respectively. All patients who received allografts are alive without disease at 38-141 months since diagnosis. For patients who received autografts, the 4-year EFS is 69%. Bone marrow involvement was a significant prognostic factor predicting for a worse survival (P = 0.02). CONCLUSION: A treatment strategy for adults with chemosensitive T-LBL that includes planned consolidation with SCT in first response produces favorable long-term outcome.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirugía , Adulto , Colombia Británica , Quimioterapia Adyuvante , Bases de Datos como Asunto , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Guías de Práctica Clínica como Asunto , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Recurrencia , Estudios Retrospectivos , Factores de Tiempo , Trasplante Autólogo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Acute myeloid leukemia (AML) presenting with a high leukocyte count has been associated with an increase in induction mortality and poor results in a number of other survival measures. However, the level at which an elevated leukocyte count has prognostic significance in AML remains unclear. In this report on a series of 375 adult (non-M3) AML patients undergoing induction chemotherapy at a single institution, leukocyte count analyzed as a continuous variable is shown to be a better predictor of induction death (ID) and overall survival (OS) than a leukocyte count of > or = 100 x 10(9)/L, a value characteristically associated with "hyperleukocytosis" (HL). In this patient cohort, a presenting leukocyte count of > or = 30 x 10(9)/L had high sensitivity and specificity for predicting ID, and both performance status (PS) and leukocyte count more accurately predicted for ID than age. Considering these parameters in newly-diagnosed AML patients may facilitate the development of strategies for reducing induction mortality.
Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Recuento de Leucocitos , Leucocitos/citología , Inducción de Remisión , Adolescente , Adulto , Anciano , Médula Ósea/metabolismo , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Curva ROC , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: We assessed the feasibility of outpatient chemotherapy and supportive care in patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: All patients receiving curative intent chemotherapy between 09/01 and 10/02 and meeting our criteria received supportive care post induction chemotherapy as well as their entire consolidation chemotherapy cycles as outpatients. Patients received antimicrobial prophylaxis; those developing episodes of fever and not meeting the criteria for admission were treated with outpatient intravenous antibiotics. RESULTS: Seventy-one cycles of induction chemotherapy were administered for newly diagnosed or relapsed AML. In 25 cycles the patient was discharged post chemotherapy prior to count recovery. Of these, 14 patients developed one or more febrile episodes as an outpatient and nine (36%) required readmission to hospital. Sixty-seven consolidation cycles were given on an outpatient basis. In 39 cycles there was one or more febrile episodes and in 14 (21%) admission was required. Infections were documented in four cases during induction and in 27 during consolidation. There were no treatment-related deaths. CONCLUSIONS: Outpatient management of AML is safe and feasible using the strategies outlined in this report.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Pacientes Ambulatorios , Adulto , Anciano , Carboplatino/administración & dosificación , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Etopósido/administración & dosificación , Estudios de Factibilidad , Femenino , Humanos , Pacientes Internos , Leucemia Promielocítica Aguda/mortalidad , Masculino , Persona de Mediana Edad , Alta del Paciente , Readmisión del Paciente/estadística & datos numéricos , Estudios Prospectivos , Inducción de Remisión , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
In all, 30 patients with CLL proceeded to myeloablative allogeneic BMT using related (n=20, 67%) or unrelated (n=10) donors, at the Princess Margaret Hospital (Toronto) (n=20) or the Leukemia/BMT Program of BC (Vancouver) (n=10), from 1989 to 2001. Median (range) interval from diagnosis to BMT was 4.8 (0.3-13) years, median number of prior therapies was three and median age 48 years. The preparative regimen included total body irradiation in 15 (50%). In all, 14 of 30 patients (47%) are alive, with median (range) follow up of 4.3 (2.4-10.5) years. All are in complete remission, two following therapy for post-BMT progression. Actuarial overall (OS) and event-free survival (EFS) at 5 years is 39% (OS 48% for related donor and 20% for unrelated donor BMT); cumulative incidence of nonrelapse mortality (NRM) and relapse is 47 and 19%, respectively. Both acute (RR=0.008, P=0.01) and chronic (RR=0.006, P=0.02) Graft-versus-host disease (GVHD) were associated with markedly decreased risk of relapse. Patients receiving grafts from unrelated donors had increased NRM (RR=3.6, P=0.02) and decreased OS (RR of death=3.4, P=0.002). Allogeneic BMT has resulted in long-term EFS in approximately 40% of patients with CLL. There is evidence for a strong graft-versus-leukemia effect associated with acute and chronic GVHD, resulting in near complete protection from relapse.
Asunto(s)
Trasplante de Médula Ósea , Enfermedad Injerto contra Huésped/mortalidad , Efecto Injerto vs Leucemia , Leucemia Linfocítica Crónica de Células B/mortalidad , Donantes de Tejidos , Adulto , Trasplante de Médula Ósea/métodos , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/etiología , Efecto Injerto vs Leucemia/efectos de la radiación , Prueba de Histocompatibilidad/métodos , Humanos , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/terapia , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión/métodos , Estudios Retrospectivos , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo , Irradiación Corporal Total/métodosRESUMEN
Endocarditis is an uncommon complication of hematopoietic stem cell transplantation (HSCT). A retrospective review of 1547 patients who underwent HSCT in Vancouver between January 1986 and December 2001 was performed. In all, 20 cases of endocarditis were identified (1.3% of all patients) with nine patients having received cryopreserved autologous stem cells, six stem cells from a histocompatible sibling and five patients stem cells from an unrelated donor. Five patients had endocarditis diagnosed while alive, a median of 6 months post-HSCT, by transthoracic (four patients) or transesophageal (one patient) echocardiography. The remaining 15 cases of endocarditis were only identified post mortem. The mitral valve was the most frequently involved (10 patients) followed by the aortic valve (six patients); multivalvular disease was noted in five patients. Of the 11 affected allogeneic HSCT patients, 10 had previously developed acute graft-versus-host disease (GVHD). Causative organisms were identified in 11 patients, while nine additional cases were felt to be thrombotic in origin. Of the 20 patients, 19 died with the sole survivor alive 10 years following an aortic valve replacement. Endocarditis is an uncommon complication of HSCT usually involving the cardiac valves on the left side of the heart and is associated with a high mortality rate.
Asunto(s)
Endocarditis/etiología , Endocarditis/mortalidad , Trasplante de Células Madre Hematopoyéticas , Adulto , Anciano , Estudios de Cohortes , Bases de Datos Factuales , Endocarditis/diagnóstico , Endocarditis/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
To establish incidence and risk factors for development of second malignant neoplasms after high-dose chemo/radiotherapy (HDT) and autologous hematopoietic stem cell transplantation (AHSCT), the case files of 800 consecutive patients who underwent AHSCT at our institution between June 1982 and December 2000 were reviewed. In all, 26 patients developed 29 second malignancies (nine myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), 16 solid tumors and four lymphoproliferative disorders (LPDs)) for a 15-year cumulative incidence of 11% (95% confidence interval (CI), 5-18%). These second tumors occurred at a median of 68 (range 1.5-177) months following AHSCT. The relative risk (RR) compared to the general population of developing a second malignancy following AHSCT was 3.3 (CI 2.2-4.7) P<0.001. The RR of developing MDS/AML, LPD and a solid tumor was 47.2 (CI 21.5-89.5) P<0.001, 8.1 (2.2-20.7) P=0.002 and 1.98 (1.1-3.2) P=0.009, respectively. In multivariate analysis, age >or=35 years at the time of AHSCT (P=0.001) and an interval from diagnosis to AHSCT >or=36 months (P=0.03) were associated with a greater risk of developing a second malignancy. Patients who have undergone HDT and AHSCT are at significant risk for developing a second malignancy and should receive indefinite follow-up.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Neoplasias Primarias Secundarias/etiología , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiología , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/etiología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/etiología , Neoplasias Primarias Secundarias/clasificación , Probabilidad , Estudios Retrospectivos , Factores de Riesgo , Trasplante AutólogoRESUMEN
Telomeres play an important role in the proliferation and senescence of normal and malignant cells. To test the role of telomerase in acute myeloid leukemia (AML), we expressed the telomerase reverse transcriptase (hTERT) gene, a dominant-negative hTERT (DN-hTERT) (D868A, D869A) gene, or a gene encoding green fluorescence protein (GFP) in the leukemia cell line K562 and in primary AML cells from different patients, using retroviral vectors. Cells transduced with hTERT exhibited elevated levels of telomerase activity compared to GFP controls, whereas cells expressing DN-hTERT had decreased telomerase activity. K562 populations transduced with DN-hTERT showed reduced clonogenicity, telomere dysfunction and increased numbers of apoptotic cells compared to GFP- or hTERT-transduced cells. Two of four clones transduced with DN-hTERT died after 30 and 53 population doublings, respectively. Transduced AML cells were tested in primary colony-forming unit (CFU) and suspension culture assays. Relative to hTERT- and GFP-transduced controls, AML cells transfected with DN-hTERT produced fewer CFU and showed lower engraftment after transplantation into sublethally irradiated beta(2)-m(-/-) nonobese diabetic/severe combined immunodeficient mice. We conclude that telomerase is limiting the growth of the leukemic cell line K562 and primary AML progenitor cells. Our data warrant further studies of the therapeutic use of telomerase inhibitors in AML.
Asunto(s)
Leucemia Mieloide/patología , Leucemia Mieloide/fisiopatología , Telomerasa/genética , Telomerasa/metabolismo , Enfermedad Aguda , Adulto , Anciano , Animales , Muerte Celular , División Celular , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Técnicas de Transferencia de Gen , Proteínas Fluorescentes Verdes , Humanos , Indicadores y Reactivos/metabolismo , Células K562 , Proteínas Luminiscentes/genética , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Trasplante de Neoplasias , Retroviridae/genéticaRESUMEN
Tumour lysis syndrome (TLS) is caused by rapid breakdown of malignant cells resulting in electrolyte disturbances and acute renal failure. TLS has rarely been described in patients with acute myelogenous leukaemia (AML). Between November 1997 and July 2001, 114 consecutive adult AML patients aged <60 yr received induction chemotherapy consisting of cytosine arabinoside 1.5 g m(-2) q 12 h x 12 doses and daunorubicin 45 mg m(-2) d(-1) x 3 doses. During induction chemotherapy (CT), seven patients (6.1%, 95% CI 2.5-12.2) developed fulminant TLS, resulting in acute renal failure; five of these seven patients had inversion of chromosome 16 [inv(16)(p13;q22)], and one patient had a biological equivalent [t(16,16)(p13;q22)]. Four of the TLS patients underwent leukapheresis for a presenting white blood cell (WBC) count > 100 x 10(9) L(-1) prior to commencing chemotherapy, and six patients subsequently required haemodialysis for a median of 2 (range 1-8) wk. One TLS patient died of intracerebral hemorrhage on day 10 and another patient of multiorgan failure on day 17. Of the other five patients, all entered a complete remission (CR) and recovered normal renal function. Four patients remain in continuous CR [median follow-up 20 (range 12-25) months]. One patient relapsed at 12 months and again developed TLS on re-induction. In univariate analysis, TLS patients were more likely to have an elevated presentation and pre-chemotherapy WBC counts, elevated serum creatinine, and uric acid levels at presentation, as well as an inv(16). In multivariate analysis, only serum creatinine and inv(16) remained statistically significant (P < 0.001 for each). Patients with an inv(16) are a unique AML subgroup at high risk for fulminant TLS.
Asunto(s)
Antineoplásicos/efectos adversos , Inversión Cromosómica , Cromosomas Humanos Par 16 , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndrome de Lisis Tumoral/etiología , Adolescente , Adulto , Antineoplásicos/administración & dosificación , Citarabina/administración & dosificación , Citarabina/efectos adversos , Daunorrubicina/administración & dosificación , Daunorrubicina/efectos adversos , Femenino , Predisposición Genética a la Enfermedad , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Síndrome de Lisis Tumoral/mortalidad , Síndrome de Lisis Tumoral/fisiopatologíaRESUMEN
The Ontario Familial Breast Cancer Registry (OFBCR) is one of six international sites of the Cooperative Familial Registry for Breast Cancer Studies collecting family history, epidemiologic information, and blood samples from families (with various patterns of familial risk) for the purpose of studying the etiology of breast cancer. To invite 2361 female breast cancer patients residing in Ontario to take part in the Registry, a package was sent that included a Family History Questionnaire. Several variations of mailing and follow-up strategies were employed. Overall, the response rate was 67%. The best response (74%) was achieved by following up our introductory package of information with a postcard 10 days later and a telephone call several weeks thereafter. Given the design of the project, which involves a considerable commitment on the part of both patients and their family members, we are impressed by the positive response of these women.
Asunto(s)
Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Recolección de Datos/métodos , Bases de Datos Factuales , Cooperación Internacional , Anamnesis/métodos , Selección de Paciente , Desarrollo de Programa/métodos , Sistema de Registros , Proyectos de Investigación , Encuestas y Cuestionarios , Neoplasias de la Mama/sangre , Bases de Datos Factuales/estadística & datos numéricos , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Ontario/epidemiología , Grupo de Atención al Paciente/organización & administración , Linaje , Sistema de Registros/estadística & datos numéricos , Factores de RiesgoRESUMEN
BACKGROUND: AML blasts differ in their functional capability, creating a hierarchy of progenitors. CD133 (AC133) is a newly described transmembrane protein expressed on CD34(+) and CD34(-) normal progenitors. We characterized the prognostic significance of CD133 expression in AML and expression of CD133 on AML progenitors thought to be responsible for maintaining this disease. METHODS: AML cells from 102 patients were analyzed for CD133 and CD34 expression, and correlated with outcome in 92 treated patients. AML cells were also FACS sorted into CD34(+)/CD133(+), CD34(+)/CD133(-), CD34(-)/CD133(+) and CD34(-)/CD133(-) subfractions, and assayed in vitro in colony-forming assay (CFU) and in suspension culture (SC) assay for up to 8 weeks, and in vivo in non-obese diabetic (NOD)/SCID mice to determine the phenotype of progenitors detected in these assays. RESULTS: CD133 expression was not correlated with event-free or overall survival, FAB subtype, cytogenetic abnormality or WBCC, but was correlated with CD34 expression. Primary AML CFU were present in all four sorted fractions. After an increasing period of time in SC, a higher proportion of cells capable of forming leukemic CFU were found in the CD34(+)/CD133(+) subfraction. Cells capable of producing leukemic engraftment in NOD/SCID mice were found in all subfractions, including the CD34(-)/CD133(-) subfraction in many patients. DISCUSSION: CD133 is not useful as a prognostic marker in AML. CD133 is expressed with CD34 on most primitive leukemic progenitors detected in vitro, however, in vivo progenitors could not be purified using CD133 in these patients.
Asunto(s)
Antígenos CD/metabolismo , Leucemia Mieloide/fisiopatología , Células Progenitoras Mieloides/metabolismo , Enfermedad Aguda , Animales , Separación Celular , Trasplante de Células , Citometría de Flujo , Humanos , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Células Progenitoras Mieloides/citología , Fenotipo , PronósticoRESUMEN
BACKGROUND: Autologous transplantation improves survival in multiple myeloma patients, however, most eventually relapse. As an attempt towards improving relapse-free survival, we designed a negative-selection purging strategy, to remove myeloma cells from leukapheresis harvests using MAbs specific for Ags on myeloma cells. METHODS: CD38 is highly expressed on myeloma plasma cells, but expressed at lower levels on normal progenitors and absent on in vivo repopulating cells. We evaluated depletion of CD38-expressing cells, with or without depletion of B-cell Ag-expressing cells. Using myeloma BM or blood cells diluted into allogeneic G-CSF primed leukapheresis cells, bispecific tetrameric Ab complexes that bind dextran iron particles were used to label and retain cells in a magnetic column, StemSep. Depletion efficacy was measured by semi-quantitative allele-specific oligonucleotide (ASO)-PCR amplification of patients' clonotypic IgH gene. RESULTS: Low (0.2 microg/mL) concentrations of anti-CD38 with CD19 and CD20 complexes depleted approximately 3-5 logs of clonotypic cells, with recovery of approximately 19% of colony-forming cells, approximately 50% primitive progenitors measured by LTCIC and retention of non-obese diabetic /SCID engrafting ability. Scale-up experiments using leukapheresis harvests and 0.5-1 x 10(10) cell capacity columns demonstrated no loss of log depletion of highly positive cells, or recovery of unlabelled cells. DISCUSSION: These results compare favorably with other purging techniques and allow the retention of most normal BM cells, including T cells, which may be important for immunity. These results support the development of a clinical trial using this strategy for purging myeloma cells.
Asunto(s)
Purgación de la Médula Ósea/métodos , Separación Celular/métodos , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Animales , Anticuerpos Monoclonales , Antígenos CD/análisis , Células de la Médula Ósea/inmunología , Trasplante de Médula Ósea , Citometría de Flujo , Células Madre Hematopoyéticas , Humanos , Separación Inmunomagnética , Leucaféresis , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mieloma Múltiple/genética , Mieloma Múltiple/inmunología , Fenotipo , Reacción en Cadena de la Polimerasa/métodos , Trasplante AutólogoRESUMEN
Despite numerous strategies, the cure of multiple myeloma remains a difficult challenge. Recent approaches have involved dose-intensive therapy followed by stem cell transplantation, most often with autologous stem cells (ASCT). Although ASCT is of benefit, it is not considered curative. Between 1988 and 1995, we utilized an aggressive three-drug conditioning regimen followed by ABMT using marrow purged with either 4-hydroperoxycyclophosphamide (4-HC) or mafosphamide (MAF). Twenty-nine of 42 patients who had first received VAD (14 patients) or VAD followed by cyclophosphamide (7 g/m2 i.v.) + dexamethasone (40 mg/day p.o. x4) + GM-CSF (15 patients) met the eligibility criteria needed to undergo bone marrow harvest and ABMT, ie < or =10% marrow plasma cells and > or =50% decrease in paraprotein level. Alpha-interferon maintenance therapy was given post ABMT. Median follow-up is 7.5 years (range 5.0-11.25). Six early and two late non-relapse deaths occurred; 15 patients have relapsed. Seven patients remain in continuous CR (five) or PR (two), including three with stage IIIB disease at diagnosis. One patient developed a soft tissue sarcoma 8 years post ASCT. Although this protocol produced excessive toxicity compared with current approaches, the results demonstrate that dose-intensive therapy and ASCT can produce durable remission in this disease. Further development of dose-intensive strategies is warranted.
Asunto(s)
Purgación de la Médula Ósea/métodos , Trasplante de Médula Ósea , Ciclofosfamida , Ciclofosfamida/análogos & derivados , Mieloma Múltiple/terapia , Adulto , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Humanos , Interferón-alfa/uso terapéutico , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
Acute graft-versus-host disease (A-GVHD) is a life-threatening complication of allogeneic stem cell transplantation (SCT), and primary therapy consists of high-dose corticosteroids. Patients who fail to respond adequately to corticosteroids require salvage treatment, with anti-T cell antibodies being the most commonly utilized group of agents. We report our institution's experience treating steroid-resistant GVHD in 36 adult patients (median age 39 years, range 24-55) with a rabbit antithymocyte globulin product (thymoglobulin). Eleven patients had undergone sibling SCT (10 histocompatible, 1 one-antigen mismatched) and 25 patients had received unrelated donor bone marrow (17 matched, 8 one-antigen mismatched); 32 patients (89%) had grade III or IV A-GVHD. Thymoglobulin was administered in two different regimens; group 1 patients (n = 13) received 2.5 mg/kg/day x 4-6 consecutive days with maintenance of all other immunosuppressives. Group 2 patients (n = 21) were given the same dose of thymoglobulin on days 1, 3, 5, and 7 with discontinuation of cyclosporine for 14 days, during which the corticosteroid dose was held at 2-3 mg/kg/day. Two patients had severe adverse reactions to thymoglobulin (hypoxemia and hypotension) and could not complete treatment, however, in the other patients, aside from transient leukopenia (25%) and and hepatic dysfunction (25%), the antibody preparation was well tolerated. Of the 34 evaluable patients, 13 patients had a complete response (38%) and 7 patients (21%) had a partial response, for an overall response rate of 59%. Response rate was higher in group 1 patients (77%) compared to group 2 patients (48%), (p = 0.15); skin GVHD was more responsive (96% of patients) than gut GVHD (46% of patients) or hepatic GHVD (36% of patients). Opportunistic infections were a significant complication, with 11 patients developing systemic fungal infections and 9 patients serious viral infections; there were seven episodes of bacteremia following thymoglobulin treatment and one fatal protozoal infection. There were 9 patients (25%) who developed post-SCT lymphoproliferative disorder (PTLD) and 4 patients who had a relapse of underlying primary malignancy; none of these patients survived. Of the 36 patients entered on the study, only 2 patients (6%) survive, at 15+ and 34+ months post-unrelated donor SCT. Although thymoglobulin is associated with an impressive response rate when administered for advanced steroid-resistant GVHD, long-term survival is uncommon, even in responders, primarily due to the high risk of developing either an opportunistic infection or a PTLD.
Asunto(s)
Corticoesteroides , Suero Antilinfocítico/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Linfocitos T/inmunología , Enfermedad Aguda , Adulto , Animales , Suero Antilinfocítico/toxicidad , Resistencia a Medicamentos , Femenino , Fiebre/etiología , Enfermedad Injerto contra Huésped/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Infecciones/etiología , Trastornos Linfoproliferativos/etiología , Masculino , Persona de Mediana Edad , Conejos , Inducción de Remisión , Terapia Recuperativa , Tasa de Supervivencia , Trasplante Homólogo/efectos adversos , Resultado del TratamientoRESUMEN
A hierarchy of progenitor cells is thought to exist in human acute myeloid leukemia (AML), with only the most primitive cells capable of proliferating to maintain the malignant clone. To further characterize this AML cell hierarchy, we evaluated the coexpression of CD34 and c-kit (CD117) on cells that are capable of long-term proliferation in vitro and in vivo.AML cells were sorted for coexpression of CD34 and c-kit (CD117) using two c-kit monoclonal antibodies (mAbs), clones 95C3 and 104D2. Sorted subfractions were evaluated for the ability to produce colony-forming units (CFU) for up to 8 weeks in suspension culture (SC) and for the capacity to repopulate NOD/SCID mice. When expression of c-kit on blood cells from 19 AML patients at diagnosis was compared using both mAbs, expression defined by 104D2 (34% +/- 6% c-kit(+)) was somewhat higher than that defined using 95C3 (18% +/- 4%). AML cells were sorted for coexpression of CD34 and c-kit using both c-kit mAbs, and the subfractions were assayed in vitro and in vivo. Whereas the majority of AML blast cells lacked expression of CD34, most AML cells capable of proliferating to produce CFU after 4 to 8 weeks in SC were CD34(+)/c-kit(-). Cultures of sorted CD34(+)/c-kit(-) cells, supplemented with steel factor, were composed of a large proportion (18% to 87%) of CD34(+)/c-kit(+) cells after 1 week, suggesting that either c-kit expression was upregulated or CD34(+)/c-kit(+) cells were produced. Moreover, the CD34(+)/c-kit(-) subfraction was found to be capable of responding to steel factor alone to produce CFU after 4 weeks in SC. In most AML patients tested (11/15), the only sorted subfraction capable of engrafting NOD/SCID mice was CD34(+)/c-kit(-). The CD34(+)/c-kit(+) subfraction from only 2 of the 15 patients and CD34(-) cells from 3 patients also engrafted the NOD/SCIDs. Only the CD34(+)/c-kit(+) subfraction of normal bone marrow engrafted. These studies suggest that primitive AML cells capable of long-term proliferation in vitro and NOD/SCID repopulation differ from primitive normal progenitor cells in their lack of surface expression of c-kit.
Asunto(s)
Regulación Leucémica de la Expresión Génica , Leucemia Mieloide/patología , Proteínas de Neoplasias/biosíntesis , Células Madre Neoplásicas/metabolismo , Proteínas Proto-Oncogénicas c-kit/biosíntesis , Enfermedad Aguda , Animales , Antígenos CD34/biosíntesis , Antígenos CD34/genética , Aberraciones Cromosómicas , Medio de Cultivo Libre de Suero/farmacología , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Humanos , Cariotipificación , Leucemia Mieloide/genética , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas de Neoplasias/deficiencia , Proteínas de Neoplasias/genética , Trasplante de Neoplasias , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Fenotipo , Proteínas Proto-Oncogénicas c-kit/genética , Factor de Células Madre/farmacología , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/metabolismoRESUMEN
BACKGROUND: Allogeneic bone marrow transplantation (BMT) has been used in patients with low-grade lymphoma (LGL) and chronic lymphocytic leukemia (CLL) with the goal of achieving long-term disease-free survival. PATIENTS AND METHODS: Twenty-nine patients with these diagnoses (LGL = 19, CLL = 10) received allogeneic BMT between September 1995 and January 1999. Median age was 42 (range 20-52) years. Twenty-three of twenty-nine patients (79%) were Ann Arbor or Rai stage IV at the time of transplant; twenty-four (83%) had never achieved complete remission (CR). Donor source was HLA-matched sibling (20), unrelated (8) and syngeneic (1). RESULTS: Seventeen patients are currently alive, a median of 29 months (range 1-85) post-BMT with a median KPS of 90%. Twenty-three of twenty-seven evaluable patients (85%) achieved CR post-BMT. Six patients had refractory/recurrent disease. Death occurred related to transplant complications in eight patients and underlying disease in four. Overall and event-free survival for the whole group is 51% and 44%, respectively. CONCLUSIONS: Allogeneic BMT for young patients with advanced stage LGL or CLL is a feasible strategy that can result in achievement of long-term disease-free survival.
Asunto(s)
Trasplante de Médula Ósea/métodos , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/terapia , Linfoma no Hodgkin/mortalidad , Linfoma no Hodgkin/terapia , Adulto , Análisis de Varianza , Trasplante de Médula Ósea/efectos adversos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Leukapheresis collections obtained following one of four mobilization regimens from 90 cancer patients were analyzed for their content of various progenitor cell types including erythroid and granulopoietic colony-forming cells in methylcellulose (total CFC), CFC-megakaryocyte (CFC-Mk), CFC detected after 10, 35 and 56 days in long-term culture (LTC), and total CD34+ cells. The number of each of these progenitor cell types collected from individual patients varied over 1000-fold. Nevertheless, within an individual leukapheresis, there was a significant correlation between the number of CD34+ cells and each progenitor type (except day 56 LTC CFC) suggesting that all of them are mobilized by a common mechanism. Patients who had previously received extensive chemotherapy and/or radiotherapy mobilized fewer of all these cell types than those who had not. For the 65 patients who proceeded to autologous transplantation, the median times to an absolute neutrophil count (ANC) of > or =0.5 x 109/l and the last platelet transfusion post transplant were 13 and 11 days, respectively, with 14 (22%) of patients having platelet recovery delayed beyond day 21. There was no significant difference between patients who had or had not received extensive chemo/radiotherapy or among the different mobilization regimens for time to neutrophil or platelet recovery or the number of platelet or red blood cell transfusions received post transplant. Threshold doses of the different cell types transplanted (per kg of patient weight) which predicted rapid platelet recovery were 2 x 106 CD34+ cells, 5 x 105 total CFC and 2.5 x 104CFC-Mk. Corresponding thresholds for progenitor activity measured in LTC could not be established. These results further support the view that standard mobilization regimens yield progenitor numbers that are, in most cases, nonlimiting for generating neutrophil and platelet recoveries within 2 to 3 weeks after myeloablative therapy. Assessment of the CD34+ cell and/or CFC content of leukapheresis collections may identify patients in whom platelet recovery is likely to be significantly delayed although CFC-Mk enumeration does not appear to offer any unique predictive advantage.