RESUMO
To determine prognosis of acute promyelocytic leukemia (APL) failing to front-line therapy with all-trans retinoic acid (ATRA) and anthracyclines, outcome of 52 patients (32 M/20 F; age: 37, 3-72) included in PETHEMA trials LPA96 and LPA99 who presented with either molecular failure (MOLrel, n=16) or hematological relapse (HEMrel, n=36) was analyzed. Salvage therapy consisted of ATRA and high-dose ara-C-based chemotherapy (HDAC) in most cases (83%), followed by stem-cell transplantation (autologous, 18; allogeneic, 10; syngeneic, 1). Fourteen patients with MOLrel (88%) achieved second molecular complete response (molCR), whereas 81% HEMrel patients responded to second-line treatment, with 58% molCR. After median follow-up of 45 months, four MOLrel and 18 HEMrel patients, respectively, experienced a second relapse. Outcome after MOLrel compared favorably to HEMrel, with longer survival (5-year survival: 64+/-14 vs 24+/-8%, P=0.01) and lower relapse risk (5-year relapse risk: 30+/-13 vs 64+/-9%; P=0.044). Additionally, age Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
, Leucemia Promielocítica Aguda/tratamento farmacológico
, Terapia de Salvação
, Adolescente
, Adulto
, Idoso
, Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
, Biomarcadores Tumorais/sangue
, Criança
, Pré-Escolar
, Terapia Combinada
, Citarabina/administração & dosagem
, Etoposídeo/administração & dosagem
, Feminino
, Transplante de Células-Tronco Hematopoéticas
, Humanos
, Idarubicina/administração & dosagem
, Estimativa de Kaplan-Meier
, Leucemia Promielocítica Aguda/sangue
, Leucemia Promielocítica Aguda/mortalidade
, Leucemia Promielocítica Aguda/patologia
, Leucemia Promielocítica Aguda/cirurgia
, Lipossomos/administração & dosagem
, Masculino
, Pessoa de Meia-Idade
, Mitoxantrona/administração & dosagem
, Neoplasia Residual
, Proteínas de Fusão Oncogênica/sangue
, Prognóstico
, Recidiva
, Indução de Remissão
, Análise de Sobrevida
, Fatores de Tempo
, Resultado do Tratamento
, Tretinoína/administração & dosagem
RESUMO
Theoretical considerations and preliminary results of clinical trials support the earlier use of autologous bone marrow transplantation (ABMT) in poor prognosis non-Hodgkin's lymphoma (NHL). A prognostic analysis of 50 patients with intermediate or high grade NHL younger than 60 years, who achieved at least one complete remission and were not treated with BMT, was performed. Patients with bulky tumor at diagnosis and/or serum LDH greater than or equal to 600 U/l do poorly with conventional chemotherapy. Twelve patients with these high-risk initial characteristics in first complete remission (CR) and six patients in second or third CR were treated with cyclophosphamide (60 mg/kg x 2) and total body irradiation (1000-1200 cGy) followed by ABMT. Overall disease-free survival was 65% at a median follow-up of 35 months. No differences were found between the first and later CR patients. The rate of toxic death was 11%. Disease-free survival after first CR was better for 1st CR ABMT patients than for a historical chemotherapy control group with similar poor prognosis features (p = 0.008). These results support the use of ABMT in selected, high-risk NHL patients in first CR.
Assuntos
Transplante de Medula Óssea , Linfoma não Hodgkin/cirurgia , Adolescente , Adulto , Antineoplásicos/uso terapêutico , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/mortalidade , Criança , Feminino , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prognóstico , Transplante AutólogoRESUMO
Interferon-alpha (IFN-alpha) is a therapy of unquestionable efficacy in chronic myeloid leukemia (CML) patients. The best dose of IFN-alpha in the treatment of CML still remains controversial. Our primary objective was to compare cytogenetic responses in patients treated with intermediate versus high doses of IFN-alpha. A multicenter randomized controlled trial was conducted involving 109 patients with untreated CML in chronic phase from 26 Spanish hospitals. Patients were assigned to receive either an intermediate (2.5 MU/m(2) per day) or high (5 MU/m(2) per day) target dose of IFN-alpha. Hydroxyurea was allowed in both groups. In total, 108 patients were analyzed, 53 in the intermediate- and 55 in the high-dose group. Median follow-up was 47.5 months. The dose of IFN-alpha actually given was lower in the intermediate-dose group (3.83 MU/day) than in the high-dose group (6.6 MU/day) ( p<0.001). The rate of complete cytogenetic response was 24.5% in the intermediate- and 12.7% in the high-dose group (NS). A partial cytogenetic response was obtained in 7.5% and 10.9%, respectively. Cox analysis did not reveal any influence of the randomization arm on cytogenetic response rate. Ten patients in each group discontinued IFN-alpha because of toxicity. Albeit not our primary objective, no differences were found in terms of survival or transformation rate between both groups. Median survival was 73 months; 64% of patients remained free of transformation at 5 years. In terms of cytogenetic response, intermediate doses of IFN-alpha are as effective as high doses in the treatment of CML.
Assuntos
Análise Citogenética , Interferon-alfa/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/economia , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Interferon-alfa/efeitos adversos , Interferon-alfa/economia , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
BACKGROUND AND OBJECTIVES: Acute myeloid leukemia (AML) is a heterogeneous group of malignant diseases, often characterized by coexistence of more than one subpopulation of blast cells. Multiparametric flow cytometry immunophenotyping has proven to be a reliable and sensitive approach for the discrimination of myeloid blast cells from residual normal cells present in bone marrow samples from AML patients and, at the same time, allows the identification of different maturation compartments among myeloid blasts. Therefore, it provides a unique tool for assessing apoptotic and multidrug resistance (MDR)-associated phenotypes in individual subsets of leukemic cells. DESIGN AND METHODS: The aim of the present study was to explore the simultaneous expression of proteins related to both apoptosis (APO2.7, bcl-2, bax) and multidrug resistance (MDR1, MRP, LRP) in the different blast cell subpopulations detected at diagnosis in a group of 72 elderly patients with AML. In addition, we included 5 bone marrow samples from healthy adult donors in the analysis. RESULTS: Immature blast cells (CD34+: subset I) showed a significantly higher level of bcl-2 expression (p <0.0001) together with a lower reactivity for APO 2.7 (p=0.02) as compared to the other more mature CD34- cell subsets. The expression of Bax parallelled that of APO 2.7, although the difference between immature CD34+ blast cells and the mature blast cell subsets did not reach statistical significance (p=0.18). These results translated into a significantly (p<0.0001) higher bcl-2/bax ratio for the CD34+ blast cells as compared to that of the two CD34- blast cell subpopulations. Regarding the expression of the multidrug resistance-associated proteins Pgp and MRP, CD34+ blast cells displayed a greater expression of both proteins as compared to the more mature CD34- AML blast cells, but differences according to maturation stage of AML blast cells did not reach statistical significance. In contrast, LRP expression was significantly lower in the more immature CD34+ blast cell subset than in the more mature ones (p=0.01). INTERPRETATIONS AND CONCLUSIONS: As far as normal bone marrow is concerned our results suggest that all blast cell subpopulations are more protected from apoptosis than their normal counterparts. We conclude that in elderly patients with AML the more immature blast cells are more resistant to apoptotic processes, which could explain why, when AML relapses, the blast cells frequently display a more immature phenotype than that observed at diagnosis. Contradictory results in multidrug resistance profile support the hypothesis that failure to respond to chemotherapeutic drugs in AML is a multifactorial phenomenon.
Assuntos
Apoptose/genética , Crise Blástica/patologia , Resistência a Múltiplos Medicamentos/genética , Leucemia Mieloide/genética , Leucemia Mieloide/patologia , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Humanos , Leucemia Mieloide/metabolismo , Análise Multivariada , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , FenótipoRESUMO
BACKGROUND AND OBJECTIVES: To analyze in patients with de novo acute promyelocytic leukemia (APL) treated with an ATRA plus anthracyclin-based protocol if the presence of additional cytogenetic aberrations to the t(15;17) influences: 1. clinical and biological presenting features; 2. disease outcome. DESIGN AND METHODS: One hundred and thirteen patients with newly diagnosed APL enrolled in the APL-96 protocol of the Spanish PETHEMA group were studied by conventional karyotyping, FISH and RT-PCR for the PML-RARa fusion. Treatment was homogeneous in all cases and consisted of anthracyclines and ATRA. RESULTS: Additional chromosome aberrations were observed in 30% of cases. The most frequent secondary changes were +8 (14 cases), and abnormalities of chromosomes 9 or 3 (4 patients each), and of chromosomes 1 and 8 (3 cases each). No clinical, biological, morphological, immunophenotypic or molecular differences were observed between the group of APLs with t(15;17) alone and the group of patients with additional changes. Patients with additional changes had a higher rates of complete remission (CR) and 4-year disease-free survival (DFS) (97%, and 97%, respectively) than patients with t(15;17) alone (CR, 70% and DFS, 84%) but these differences were not statistically significant. INTERPRETATION AND CONCLUSIONS: Patients with APL and additional cytogenetic abnormalities do not show different clinical, biological, morphological or molecular features as compared to patients with t(15;17) alone. The prognosis of patients with APL and t(15;17) alone and those with additional changes is similar in both groups. This study indicates that there is no rationale for administering more intensive treatment in APL patients with additional cytogenetic abnormalities receiving ATRA plus anthracycline-based chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Análise Citogenética , Leucemia Promielocítica Aguda/genética , Adolescente , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Criança , Aberrações Cromossômicas , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Resultado do Tratamento , Tretinoína/administração & dosagemRESUMO
Of 167 newly diagnosed acute promyelocytic leukaemia patients, 83 patients were long (L)-form (50%), eight variable (V)-form (5%) and 76 short (S)-form (45%). The V-form and S-form groups presented a significantly higher percentage of patients with white blood cell counts > 10 x 10(9)/l (P < 0.05). The S-form cases displayed a significantly higher number of cases with M3v microgranular features (P = 0.005) and CD34 expression (P < 0.0001). There were no differences between the three isoforms in complete remission (CR) rate (overall CR 90%), but the 3-year disease-free survival was lower for V-form cases than it was for L- and S-form cases (62% vs. 94% and 89%, P = 0.056). We conclude that the V-form and S-form types are associated with some negative prognostic features at diagnosis. However, our data were only able to demonstrate an association with adverse prognosis in the V-form type and, moreover, as the number of cases was limited, needs to be confirmed in large, uniformly treated series.