RESUMO
We evaluated the impact of genomic polymorphisms in folate-metabolizing, DNA synthesis and DNA repair enzymes on the clinical outcome of 108 patients with myelodysplastic syndromes (MDS) receiving best supportive care (BSC) or azacitidine. A statistically significant association between methylenetetrahydrofolate reductase (MTHFR) 677T/T, thymidylate synthase (TS) 5'-untranslated region (UTR) 3RG, TS 3'-UTR -6 bp/-6 bp, XRCC1 399G/G genotypes and short survival was found in patients receiving BSC by multivariate analysis (P<0.001; P=0.026; P=0.058; P=0.024). MTHFR 677T/T, TS 3'-UTR -6 bp/-6 bp and XRCC1 399G/G genotypes were associated with short survival in patients receiving azacitidine by multivariate analysis (P<0.001; P=0.004; P=0.002). We then performed an exploratory analysis to evaluate the effect of the simultaneous presence of multiple adverse variant genotypes. Interestingly, patients with ⩾1 adverse genetic variants had a short survival, independently from their International Prognostic Scoring System (IPSS) and therapy received. To our knowledge, this is the first study showing that polymorphisms in folate-metabolizing pathway, DNA synthesis and DNA repair genes could influence survival of MDS patients.
Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Timidilato Sintase/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Cuidados Paliativos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Epidemiological and clinical information on primary plasma cell leukemia (pPCL) are rarely reported. The aims are to evaluate the clinical features, prognostic factors, and efficacy of treatments in pPCL. PATIENTS AND METHODS: A multicenter retrospective cohort study was carried out from January 2000 to December 2008 in 26 Italian hematology divisions. A total of 128 cases of plasma cell leukemia were collected, and 73 of them (57%) were classified as primary (male/female 43/30). RESULTS: Sixty-four patients had at least 1 sign of end-organ damage and 10 had extramedullary localization. One patient died early; of the remaining patients, 36 (50%) received anthracycline-based regimens as first-line therapy, 17 (24%) single alkylating agents, and 30 (42%) bortezomib or thalidomide as additional (n = 11) or unique treatments (n = 19). Twenty-three patients (31%) underwent autologous and/or allogeneic hematopoietic stem cell transplantation (HSCT). The median overall survival (OS) was 12.6 months; complete or partial response was achieved in 22 (30%) and 18 patients (25%), respectively; the median duration of response (DOR) was 16.4 months. HSCT patients had a longer OS and DOR (median 38.1 and 25.8 months, respectively) compared with nontransplanted patients (9.1 and 7.3 months, respectively, P < 0.001). OS was influenced by nonresponse to treatment, hypoalbuminemia, and HSCT. DOR was favorably influenced only by HSCT. CONCLUSIONS: pPCL is an aggressive disease with a poor prognosis and a low response rate to conventional therapy. HSCT is effective, increasing OS and DOR by 69% and 88%, respectively. The use of bortezomib and thalidomide may improve outcomes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Plasmocitária/terapia , Recidiva Local de Neoplasia/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/administração & dosagem , Ácidos Borônicos/administração & dosagem , Bortezomib , Estudos de Coortes , Terapia Combinada , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Pirazinas/administração & dosagem , Estudos Retrospectivos , Taxa de Sobrevida , Talidomida/administração & dosagem , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
Post-remission therapy in acute myeloid leukemia (AML) remains problematic. It has been demonstrated that younger patients can maintain longer complete remissions (CR) with aggressive post-remission therapies after induction treatment: allogeneic (allo), autologous (auto) stem cell transplantation (SCT), or intensive chemotherapy (ICC). The purpose of our study was to identify the most important randomized and controlled studies comparing these three therapeutic options, in order to draw conclusions and possible suggestions for post-remission therapy of AML, according to the evidence based medicine (EBM) rules. We performed an exhaustive analysis of the literature, searching either in electronic databases or among the references of the identified articles (hand searching). We searched the MEDLINE computer database for reports from 1985 through January 2005 and selected for analysis the clinical trials conducted over adults affected by newly diagnosed AML aged less than 65 years. The study design had to satisfy strict methodological criteria and must consider global mortality and/or disease free survival as primary outcomes. Overall we found 7750 papers; by using the limits "clinical trial" as publication type, "all adults 19+ years", we were able to select 344 papers. Among these, a further selection was made, based on two main clinical queries: 1) is auto-SCT superior to ICC/no other therapy in improving DFS and/or OS in adult AML patients in first CR? 2) is allo-SCT superior to auto-SCT/other therapeutic options in improving DFS and/or OS in adult AML patients in first CR? Concerning the first query, a possible advantage of auto-SCT over ICC was not clearly supported by data from clinical trials; there is no evidence that auto-SCT is superior in terms of OS to chemotherapy. Nevertheless, the reported TRM has been significantly reduced within the past years. Thus, the percentage of patients suitable for auto-SCT in CR has increased. Moreover, the scarce data concerning the comparison between auto-SCT and chemotherapy in different subsets of patients are unable to suggest a differentiated approach in patients with high-risk, standard-risk or low-risk AML. Data from the literature show that patients with unfavorable risk disease are more often addressed to allo-SCT and patients with low-risk disease receive more often intensive consolidation chemotherapy. Concerning the second query, interpretation of data from the main prospective studies about the role of allo-SCT in previously untreated AML is not easy. The first problem is the lack of real randomized clinical trials; in fact, according to the reported studies, AML patients generally receive allo-SCT on the basis of donor availability (the so called "genetic randomization"). The second problem is the frequent absence of intention to treat analysis. Despite methodological limitations, it was possible to compare allo-SCT with auto-SCT on a donor versus no-donor analysis and within risk groups. No overall benefit of allo-grafting on survival was demonstrated by any trial. In conclusion, the EBM approach highlighted the limitations observed in the published studies concerning consolidation therapy in AML; some suggestions, emerging from non-randomized, as well as randomized studies, are adequate, but not conclusive. This point, coupled with the intrinsic complexity to study AML biological heterogeneity, is probably a major obstacle to draw conclusive evidences for consolidation therapy in AML. These observations should plan to address new randomized studies on AML therapy; however, due to the emergence of genetic subgroups and new drugs targeting specific abnormalities, these trials should probably be designed directly focusing on the single entities. In this way, the cure of AML could eventually become the cure of each specific AML subset with its peculiar biological, molecular and prognostic features.
Assuntos
Medicina Baseada em Evidências , Leucemia Mieloide Aguda/tratamento farmacológico , Transplante de Células-Tronco/métodos , Adulto , Fatores Etários , Antineoplásicos/farmacologia , Ensaios Clínicos como Assunto/métodos , Intervalo Livre de Doença , Humanos , Indução de Remissão , Projetos de Pesquisa , Transplante Homólogo , Resultado do TratamentoRESUMO
Selective elimination of multidrug resistance-positive cells (LoVo/Dx) was obtained by using the monoclonal antibody MRK 16, which recognizes a surface epitope of the Mr 170,000 glycoprotein, and a sheep anti-mouse immunoglobulin antibody, conjugated to the ribosome-inactivating protein saporin 6. The killing was greatly decreased or even abolished by adding the monoclonal antibody at a 100-fold concentration. Both the MRK 16 and anti-mouse saporin 6 conjugate did not show any killing activity when they were used separately. In cell suspensions composed of 90% normal bone marrow cells and 10% multidrug resistance-positive cells, the monoclonal antibody MRK 16 followed by the anti-mouse immunotoxin caused the elimination of 99% multidrug resistance-positive cells, as revealed by immunofluorescence and immunocytochemistry as well as by a clonal assay. Human normal hematopoietic precursors (granulomonocytic colony-forming units, erythroid burst-forming units, and multipotent granulomonocytic, erythroid, and megakaryocytic-forming units) were not affected by the MRK 16 plus immunotoxin treatment. This technique might be suitable for ex vivo bone purging in an appropriate clinical setting, such as autologous bone marrow transplantation.
Assuntos
Anticorpos Monoclonais , Antineoplásicos Fitogênicos/farmacologia , Células da Medula Óssea , Resistência a Medicamentos , Imunotoxinas/farmacologia , Glicoproteínas de Membrana/imunologia , N-Glicosil Hidrolases , Proteínas de Plantas/farmacologia , Medula Óssea/efeitos dos fármacos , Linhagem Celular , Neoplasias do Colo , Ensaio de Unidades Formadoras de Colônias , Doxorrubicina/farmacologia , Epitopos/análise , Humanos , Peso Molecular , Proteínas Inativadoras de Ribossomos Tipo 1 , Saporinas , Células Tumorais Cultivadas/citologia , Células Tumorais Cultivadas/efeitos dos fármacos , Ensaio Tumoral de Célula-TroncoRESUMO
Different types of acute myeloid leukemia blast cells were induced to differentiate in vitro with all-trans-retinoic acid (ATRA) and vitamin D3 (VD). M0/M1 leukemic cells are not sensitive to differentiating agents, whereas M3 leukemic cells are induced to undergo granulocytic differentiation after ATRA treatment but are not sensitive to VD. M2 leukemic blast cells behave differently because they undergo monocytic differentiation with both the differentiation inducers. To gain some insight into the maturation of M2-type leukemic cells, we studied the molecular mechanisms underlying monocytic differentiation induced by ATRA and VD in spontaneous M2 blast cells as well as in Kasumi-1 cells (an acute myeloid leukemia M2-type cell line). Our results indicate that ATRA as well as VD efficiently increases the nuclear abundance of VD receptor (VDR) and promotes monocytic differentiation. VDR is functionally active in ATRA-treated Kasumi-1 cells because it efficiently heterodimerizes with retinoid X receptor, binds to a DR3-type vitamin D-responsive element, and activates the transcription of a vitamin D-responsive element-regulated reporter gene. Consistent with these findings, VD-responsive genes are induced by ATRA treatment of Kasumi-1 cells, suggesting that the genetic program underlying monocytic differentiation is activated. The molecular mechanism by which ATRA increases the nuclear abundance of a functional VDR is still unknown, but our data clearly indicate that the M2 leukemic cell context is only permissive of monocytic differentiation.
Assuntos
Calcitriol/farmacologia , Leucemia Mieloide Aguda/patologia , Monócitos/citologia , Células-Tronco Neoplásicas/metabolismo , Receptores de Calcitriol/fisiologia , Receptores do Ácido Retinoico/metabolismo , Fatores de Transcrição/metabolismo , Tretinoína/farmacologia , Doença Aguda , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula , Núcleo Celular/metabolismo , DNA/metabolismo , Dimerização , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Células HL-60/metabolismo , Humanos , Leucemia Mieloide/patologia , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/patologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Multimerização Proteica , Receptores de Calcitriol/genética , Proteínas Recombinantes de Fusão/fisiologia , Sequências Reguladoras de Ácido Nucleico , Receptor alfa de Ácido Retinoico , Receptores X de Retinoides , Transcrição Gênica , Células Tumorais CultivadasRESUMO
The increase in the incidence of acute myeloid leukemia (AML) may suggest a possible environmental etiology. PM2.5 was declared by IARC a Class I carcinogen. No report has focused on particulate environmental pollution together with AML. The study investigated the presence and composition of particulate matter in blood with a Scanning Electron Microscope coupled with an Energy Dispersive Spectroscope, a sensor capable of identifying the composition of foreign bodies. 38 peripheral blood samples, 19 AML cases and 19 healthy controls, were analyzed. A significant overload of particulate matter-derived nanoparticles linked or aggregated to blood components was found in AML patients, while almost absent in matched healthy controls. Two-tailed Student's t-test, MANOVA and Principal Component Analysis indicated that the total numbers of aggregates and particles were statistically different between cases and controls (MANOVA, P<0.001 and P=0.009 respectively). The particles detected showed to contain highly-reactive, non-biocompatible and non-biodegradable metals; in particular, micro- and nano-sized particles grouped in organic/inorganic clusters, with statistically higher frequency of a subgroup of elements in AML samples. The demonstration, for the first time, of an overload of nanoparticles linked to blood components in AML patients could be the basis for a possible, novel pathogenetic mechanism for AML development.
Assuntos
Poluentes Ambientais/efeitos adversos , Leucemia Mieloide Aguda/etiologia , Nanopartículas/efeitos adversos , Análise Química do Sangue , Estudos de Casos e Controles , Poluentes Ambientais/sangue , Feminino , Humanos , Leucemia Mieloide Aguda/epidemiologia , Masculino , Metais/sangue , Nanopartículas/análiseRESUMO
Fifty patients with recurrent Hodgkin's disease have been treated with high-dose therapy followed by autologous bone marrow transplantation. Forty-one patients had extranodal sites of relapse and 31 patients had constitutional symptoms. Two patients had been treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), lomustine, vinblastine, procarbazine, and prednisone (CcVPP), and radiation; 16 patients with MOPP, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), radiation, and lomustine, etoposide, and prednisone (CEP); 20 patients with alternating MOPP/ABVD, and 12 patients with alternating MOPP/ABVD followed by CEP and radiation. Eighteen patients had progressive disease during alternating MOPP/ABVD protocol alone or during conventional salvage therapy; 32 patients had had a complete remission with first-line therapy but later relapsed, 25 of them having received conventional salvage therapy; 12 achieved no response or progression ("resistant-relapse" patients); and 13 responded partially or completely ("sensitive-relapse" patients). Complete remission occurred in 24 patients (48%) with a median duration of 24 months and 16 patients (32%) achieved partial response with a median duration of 9 months, for an overall response rate of 80%. Ten patients failed to respond and died in progressive disease 1 to 10 months (median, 6 months) after transplantation. Toxicity was significant including infections (20%), liver enzymes and alkaline phosphatase elevations (100%), and carmustine lung toxicity (7%). There were two treatment-related deaths; one patient died of Pseudomonas aeruginosa septicemia and another patient died of cerebral hemorrhage. These results validate the procedure of high-dose therapy followed by autologous bone marrow transplantation in inducing remission in these advanced, highly-treated patients. Clearly, the question of whether high-dose therapy and transplantation will eventually supersede new conventional salvage therapies will be addressed after controlled clinical studies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Doença de Hodgkin/tratamento farmacológico , Adulto , Bleomicina/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Humanos , Itália , Lomustina/administração & dosagem , Masculino , Mecloretamina/administração & dosagem , Prednimustina/administração & dosagem , Prednisona/administração & dosagem , Procarbazina/administração & dosagem , Transplante Autólogo , Vimblastina/administração & dosagem , Vincristina/administração & dosagemRESUMO
PURPOSE: To assess the safety, tolerability, and hematopoietic efficacy of sequential and concomitant administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human interleukin-3 (rhIL-3), to accelerate reconstitution of hematopoiesis following myeloablative chemotherapy and autologous bone marrow transplantation (ABMT) for heavily pretreated lymphoma patients. PATIENTS AND METHODS: Fifty-four consecutive patients with refractory or relapsed non-Hodgkin's lymphoma (NHL; n = 30) and Hodgkin's disease (HD; n = 24) were studied. Two different conditioning regimens were used for ABMT: carmustine, cyclophosphamide, etoposide, and cytarabine (BAVC) and carmustine, melphalan, etoposide, and cytarabine (BEAM) for NHL and HD, respectively. Patients were enrolled sequentially onto one of three treatment groups: group 1, G-CSF (5 micrograms/kg/d subcutaneously [SC]) from day +1 after reinfusion of autologous marrow (n = 23); group 2, G-CSF from day +1 combined with IL-3 (10 micrograms/kg/d SC) from day +6 (n = 22, overlapping schedule); and group 3, G-CSF treatment discontinued at day +6 before initiation of IL-3 administration (n = 9, sequential schedule). In the three groups, growth factor(s) was administered until the granulocyte count was greater than 0.5 x 10(9)/L for 3 consecutive days. RESULTS: The study cytokines were generally well tolerated. No side effects were observed when G-CSF was given alone. Four of 31 patients (12.9%) who received SC IL-3 had one severe adverse event defined as World Health Organization (WHO) grade 3 to 4 toxicity (fever, n = 2; pulmonary toxicity, n = 2) and were withdrawn from the study. Groups 2 and 3 did not differ as for treatment tolerability, whereas we observed a trend toward a faster hematopoietic recovery when IL-3 was administered concomitant with G-CSF from day 6 (ie, group 2). Pooled together, patients who received IL-3 showed a median time to achieve a granulocyte count greater than 0.1 and greater than 0.5 x 10(9)/L of 8 and 11 days, respectively. The median time to an unsupported platelet count greater than 20 and 50 x 10(9)/L was 15 and 20 days, respectively, and only one patient did not reach a normal platelet count. The median number of days to hospital discharge was 16 after ABMT (range, 12 to 29). When the hematologic reconstitution of patients in groups 2 and 3 was compared with that of patients in group 1, the addition of IL-3 resulted in a significant improvement of multilineage hematopoietic recovery, lower transfusion requirements, a lower number of documented infections, and shorter hospitalizations. CONCLUSION: We conclude that the combination of G-CSF and IL-3 is safe and well tolerated in intensively pretreated lymphoma patients, undergoing ABMT and results in rapid hematopoietic recovery following myeloablative chemotherapy.
Assuntos
Transplante de Medula Óssea , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Hematopoese , Doença de Hodgkin/terapia , Interleucina-3/administração & dosagem , Linfoma não Hodgkin/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Feminino , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Doença de Hodgkin/fisiopatologia , Humanos , Interleucina-3/efeitos adversos , Linfoma não Hodgkin/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Condicionamento Pré-Transplante , Transplante AutólogoRESUMO
PURPOSE AND METHODS: Optimization of remission-induction and postremission therapy in elderly individuals with acute myeloid leukemia (AML) was the subject of a randomized study in patients older than 60 years. Remission-induction chemotherapy was compared between daunomycin (DNR) 30 mg/m2 on days 1, 2, and 3 versus mitoxantrone (MTZ) 8 mg/m2 on days 1, 2, and 3, both plus cytarabine (Ara-C) 100 mg/m2 on days 1 to 7. Following complete remission (CR), patients received one additional cycle of DNR or MTZ chemotherapy and were then eligible for a second randomization between eight cycles of low-dose (LD)-Ara-C 10 mg/m2 subcutaneously every 12 hours for 1 2 days every 6 weeks or no further treatment. RESULTS: A total of 242 patients was randomized to DNR and 247 to MTZ. Median age of both study groups was 68 years. Secondary AML was documented in 26% and 25% of patients in either arm. The probability of attaining CR was greater (P = .069) with MTZ (47%) than with DNR (38%). Median duration of neutropenia was 19 (DNR) and 22 days (MTZ). The greater response rate to MTZ therapy correlated with reduced occurrence of chemotherapy resistance (32% v 47%, P = .001). With a median follow-up of 6 years, 5-year disease-free survival (DFS) is 8% in each arm. Overall survival estimates are not different between the groups (6% v 9% at 5 yrs). Poor performance status at diagnosis, high WBC count, older age, secondary AML, and presence of cytogenetic abnormalities all had an adverse impact on survival. Secondary AML and abnormal cytogenetics predicted for shorter duration of CR. Among complete responders, 74 assessable patients were assigned to Ara-C and 73 to no further therapy. Actuarial DFS was significantly longer (P = .006) for Ara-C-treated (13% [SE = 4.0%] at 5 years) versus nontreated patients (7% [SE = 3%]), but overall survival was similar (P = .29): 18% (SE = 4.6%) versus 15% (SE = 4.3%). Meta-analysis on the value of Ara-C postremission therapy confirms these results. CONCLUSION: In previously untreated elderly patients with AML, MTZ induction therapy produces a slightly better CR rate than does a DNR-containing regimen, but it has no significant effect on remission duration and survival. Ara-C in maintenance may prolong DFS, but it did not improve survival.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Daunorrubicina/administração & dosagem , Leucemia Mieloide/tratamento farmacológico , Mitoxantrona/administração & dosagem , Doença Aguda , Idoso , Citarabina/administração & dosagem , Daunorrubicina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitoxantrona/efeitos adversos , Prognóstico , Indução de Remissão , Análise de SobrevidaRESUMO
It has been reported that the adenine nucleoside analogue fludarabine is able to increase the phosphorylation and the cytotoxicity of cytosine arabinoside (Ara-C) in different leukemic models, both in vitro and in vivo. In poor prognosis acute myeloid leukemia (AML), the combination of fludarabine with Ara-C and granulocyte colony-stimulating factor (G-CSF) has proven to be a highly effective regimen. In this study we aimed to further investigate the effects of this drug combination. In vitro, on fresh AML cells from ten patients, our results confirm an additive cytotoxic effect displayed by fludarabine + Ara-C, as demonstrated by isobologram analysis of the data. The addition of G-CSF significantly increased the efficacy of the drug combination. These effects appeared to be related to an increased incorporation of [3H]Ara-C into cellular DNA in the presence of fludarabine + G-CSF. Furthermore, the quantitative evaluation of programmed cell death (apoptosis) showed that fludarabine + Ara-C + G-CSF induce apoptosis to a higher degree than either compound alone. This finding suggests that cooperative induction of apoptosis could be the potential mechanism of action of this drug combination.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Citarabina/farmacologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Leucemia Mieloide Aguda/patologia , Vidarabina/análogos & derivados , Medula Óssea/patologia , Citarabina/metabolismo , DNA de Neoplasias/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Leucemia Mieloide Aguda/metabolismo , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/metabolismo , Células Tumorais Cultivadas/patologia , Vidarabina/farmacologiaRESUMO
Twenty-eight patients with poor prognosis acute myeloid leukemia (AML) received therapy with two courses of fludarabine 30 mg/m2/day + ara-C 2 g/m2/day (days 1-5) and G-CSF 5 mg/kg/day (FLAG) (from day 0 to polymorphonuclear recovery). Eighteen patients were considered 'refractory' (eight primarily resistant, five relapsing within 6 months of initial remission, or at a second relapse; five relapsing after an autologous bone marrow transplantation procedure. Ten cases were defined 'secondary' AML (diagnosis of AML made after a preexisting diagnosis of: myelodysplastic syndrome: five cases; myelodysplastic syndrome after therapy for breast cancer: one case; previously untreated, and concomitant, non-Hodgkin's lymphoma: two cases; Hodgkin's disease treated with chemoradiotherapy: one case). Overall, 15 patients (58%) achieved a complete remission (CR). Two patients died of infection during induction, and 11 had resistant disease. Analyzing the data in relation to selected host and disease characteristics, the response varied widely. The highest CR rates (89%) were obtained in secondary AML; in particular, two cases of 'second-primary' (concomitant with low-grade non-Hodgkin's lymphoma) AML obtained CR for both diseases. Refractory AML differed widely for response: high CR rate (75%), although with short mean CR duration for primary resistance AML, and very poor response (11% CR) for relapsed (early, second, after ABMT) cases. Interestingly, a slow kinetic of leukemic growth in vivo before FLAG administration was significantly related to the response and outcome (p = 0.0002). Hematological and nonhematological toxicities were acceptable. In conclusion, the FLAG regimen has significant antileukemic activity and acceptable toxicity especially in secondary AML, both with and without coexisting lymphoid malignancy.
Assuntos
Citarabina/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Leucemia Mieloide/tratamento farmacológico , Vidarabina/análogos & derivados , Doença Aguda , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária , Vidarabina/administração & dosagemRESUMO
In this study, we evaluated the in vitro growth of normal hematopoietic progenitors (CFU-GM, BFU-E, CFU-GEMM, CFU-meg) stimulated by optimal sources of colony stimulating activity in the absence or presence of 10(-6) M all-trans retinoic acid (ATRA). ATRA alone did not show any colony-stimulating ability when added in culture to partially purified bone marrow populations. On the other hand, it significantly increased the number of CFU-GM (p = 0.003) and both the number (p = 0.009) and size (p = 0.002) of CFU-meg in the presence of appropriate colony-stimulating activity. Since ATRA had only modest stimulatory effects on purified CD34+ cells, the megakaryocyte colony-stimulating activity of ATRA was mainly due to an increased production of endogenous cytokines by bone marrow accessory cells. In parallel experiments, the in vitro growth of the different hematopoietic progenitors was evaluated in 28 patients affected by acute non-lymphoid leukemia (ANLL), mainly acute promyelocytic leukemia (APL). Bone marrow cells were harvested after remission induction obtained: (i) in ten APL patients treated with ATRA followed by one chemotherapy cycle (CHT) (3/7: Daunorubicin+Ara-C): group A ('ATRA/CHT'); (ii) eight APL patients treated with one CHT cycle alone (3/7 as above): group B ('APL-CHT'); (iii) in ten ANLL-non-APL patients after one CHT cycle (3/7 as above): group C ('ANLL-CHT'). The number of the different hematopoietic progenitors, and in particular CFU-GM and CFU-meg, was significantly higher in APL patients treated with ATRA plus CHT (group A) compared to APL (group B) or ANLL-non-APL (group C) patients treated with CHT alone (CFU-GM: p = 0.01; CFU-meg: p = 0.03). Our data demonstrate that ATRA is able to potentiate both normal and APL megakaryocytopoiesis and suggest that the in vivo administration of ATRA could be beneficial in other pathological conditions, where the megakaryocyte progenitor cell compartment is impaired.
Assuntos
Células-Tronco Hematopoéticas/efeitos dos fármacos , Leucemia Promielocítica Aguda/tratamento farmacológico , Megacariócitos/efeitos dos fármacos , Tretinoína/farmacologia , Antígenos CD/metabolismo , Antígenos CD34 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Células da Medula Óssea , Ensaio de Unidades Formadoras de Colônias , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Promielocítica Aguda/patologia , Megacariócitos/citologia , Megacariócitos/patologia , Tretinoína/uso terapêuticoRESUMO
Increased neoangiogenesis has been reported in myelofibrosis with myeloid metaplasia (MMM). Thus we studied the effects of thalidomide, an antiangiogenic drug, in 12 MMM patients. Before treatment, all the cases showed a significantly increased micro-vessel density (MVD); in all eight tested cases bFGF and VEGF plasma levels were higher than controls. All patients presented disease progression in the last 3 months with standard therapy, regarding splenomegaly, anemia and/or thrombocytopenia and/or hyperleukocytosis. Thalidomide was administered at daily doses increasing from 100 to 600 mg. Eleven out of 12 patients were evaluable. No progression of disease was seen during the treatment in any case. In particular, spleen size decreased in 7/11 patients, anemia improved in 3/4 (two are now transfusion independent), thrombocytopenia in 2/2 and hyperleukocytosis in 2/5 patients. Side-effects were frequent, although not severe. After treatment, VEGF and bFGF plasma levels varied widely and in selected cases decreased. In particular, VEGF and/or bFGF decreased in 4/5 responders and in 1/3 non-responders. Moreover, MVD significantly decreased in all the responders evaluated after treatment. We conclude that thalidomide is a feasible therapy in MMM patients and looks promising at least to control the growth progression of disease.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Talidomida/uso terapêutico , Adulto , Idoso , Medula Óssea/patologia , Fatores de Crescimento Endotelial/sangue , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Linfocinas/sangue , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neovascularização Patológica/tratamento farmacológico , Projetos Piloto , Mielofibrose Primária/patologia , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Homoharringtonine (HHT) is a cephalotaxine alkaloid that showed clinical efficacy in the chronic phase of chronic myeloid leukemia (Ph1+CML). As a single agent, it resulted in effectively controlling leukocytosis and in producing sporadic karyotypic conversions; its clinical use in combination with interferon (IFN-alpha) for the treatment of CML could thus be considered. In this study we evaluated the growth inhibition and the induction of apoptosis determined by HHT alone and in combination with IFN-alpha and cytosine arabinoside (Ara-C) on normal and CML (both in chronic, CML-CP and in blastic phase; CML-BP) hematopoietic progenitors. HHT is able to determine a dose-dependent cell growth inhibition; evaluation of cytotoxic activity on semisolid cultures showed an activity significantly higher on CML-CP than on normal cells (P = 0.02 for HHT 50 ng/ml and P = 0.01 for HHT 200 ng/ml). HHT exerted a synergistic effect with IFN-alpha, Ara-C and IFN-alpha + Ara-C in inhibiting CML-CP colony growth; the same activity was demonstrated by the combination of HHT with Ara-C and by the triple combination, but not by HHT + IFN-alpha, on normal myeloid progenitors. The triple combination only was able to exert a synergistic effect in CML-BP. The induction of apoptosis resulted HHT dose-dependent in CML-CP and normals; at higher drug concentrations (100-200-1000 ng/ml), HHT induced a significant increase of apoptotic cells (for normals: P = 0.04, P = 0.02 and P = 0.04; for CML-CP: P = 0.01, P = 0.01 and P = 0.04, respectively); no significant changes were observed in CML-BP. In conclusion, the differences in cytotoxic effect and apoptosis induction observed, depending on the various phases of CML, add experimental evidence to the different clinical results between the chronic phase, where the clone is responsive to HHT, and the acute phase, where the drug is ineffective. The in vitro synergism of HHT with Ara-C and IFN-alpha in CML-CP suggests further evaluation in the clinical setting.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Citarabina/farmacologia , Harringtoninas/farmacologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Interferon-alfa/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Adulto , Crise Blástica , Medula Óssea/patologia , Células da Medula Óssea , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaio de Unidades Formadoras de Colônias , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Mepesuccinato de Omacetaxina , Humanos , MasculinoRESUMO
All-trans retinoic acid (ATRA), alone or combined with chemotherapy (CHT) is widely used to induce complete remission (CR) in newly diagnosed acute promyelocytic leukemia (APL). If used alone, ATRA results in a substantial proportion of CRs. To maintain remission further, ATRA is commonly used with cycles of CHT, frequently followed by autologous (auto) or allogeneic (allo) stem cell transplantation (SCT), as early reports have shown that the continuous administration of ATRA as single therapy almost invariably leads to relapse in a short period of time (months). Pharmacokinetic studies have shown that induced resistance to ATRA is frequently suppressed by the intermittent use of the drug. In this study we applied an intermittent therapeutic protocol with ATRA in five APL patients who were either molecularly refractory after combined ATRA/CHT treatment, or relapsed, or at diagnosis, but not eligible for the combination treatment because of previous toxicity. They were treated with ATRA (45 mg/m2/day) for 21 days. The treatment was then prolonged continuously for 1 week every 2 weeks. Molecular analysis was performed by qualitative and quantitative reverse transcription-polymerase chain reaction (RT-PCR). All patients obtained molecular remission, as assessed by qualitative RT-PCR, in a median of 3 months (range 1-15). Quantitative RT-PCR confirmed these data, showing a progressive reduction (1 or 2 logs) to a 'negligible quantity' of PML-RARalpha fusion transcript (ratio PML-RARalpha/ABL x 10(4) ABL < 10(-1)) in all but one patient treated with pulsed ATRA therapy. These data were confirmed with qualitative and quantitative RT-PCR. After a median follow-up of 17 months from the start of ATRA therapy, 4/5 patients (80%) are in continuous complete molecular remission. To our knowledge, this is the first clinical observation that intermittent ATRA therapy (without chemotherapy) is effective not only in inducing but also in maintaining long-term molecular remission in APL patients. This approach could therefore be effective, if confirmed in larger series, in relapsed/refractory patients unsuitable for high-dose therapy and SCT; it may be proposed as induction therapy for selected older APL patients if considered not to be eligible for combined ATRA/CHT due to inadequate performance status or concurrent disease.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Proteínas de Neoplasias/biossíntese , Proteínas de Fusão Oncogênica/biossíntese , Tretinoína/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Esquema de Medicação , Feminino , Seguimentos , Humanos , Cinética , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Neoplasia Residual , Proteínas de Fusão Oncogênica/genética , Projetos Piloto , RNA Neoplásico/biossíntese , Indução de Remissão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tretinoína/administração & dosagemRESUMO
In a randomized phase II study, patients with myelodysplastic syndromes (MDS) with 10-30% blasts in the bone marrow and hematopoietic failure were treated with low-dose Ara C (2 x 10 mg/m2 subcutaneously (s.c.) days 1-14) and rhGM-CSF (fully glycosylated, Sandoz/Schering-Plough, 2 x 150 micrograms protein/day s.c.) given either following Ara C (days 15-21) or simultaneously (days 8-14) for 1-5 cycles. 108 patients with a median age of 65 years, range 17-80 years and refractory anemia with an excess of blasts (RAEB, n = 54), RAEB with transformation (RAEBt, n = 50) or with chronic myelomonocytic leukemia (CMML, n = 4) were evaluable. Complete remission was achieved in 15 cases (14%), 11 had a partial response (10%), and 16 a minor response (15%). Stable disease was reached in 35 cases (32%). There were 16 cases of toxic death (15%), progression occurred in 15 patients (14%). No differences existed between the two treatment arms with respect to response and duration of response. Prognostic factors for poor response included the presence of cytogenetic abnormalities and a history of previous blood transfusions. Major adverse events during treatment were hemorrhage (55%), infections (54%), and fever associated with GM-CSF administration (40%). The overall response rate ws 39%, median duration was 12.5 months from start of treatment which allowed responding patients to lead good quality life without further therapy. The question whether the combination is indeed superior to LD-Ara C alone is not settled but will be evaluated in an ongoing clinical trial.
Assuntos
Citarabina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Leucemia/etiologia , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Citarabina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Humanos , Leucemia/prevenção & controle , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Fatores de RiscoRESUMO
Treatment of P190BCR-ABL+ acute lymphoblastic leukemia (ALL) patients remains problematic: one possibility is to use biologic response modifiers such as alpha-interferon (alpha-IFN), which is known to be active in chronic myeloid leukemia (CML). We used alpha-IFN to treat 10 adult P190BCR-ABL+ ALL patients (eight newly diagnosed; two in first relapse). All received a remission induction chemotherapy (modified L-20 protocol). Patients achieving morphological, immunological and cytogenetic complete remission (CR) were then submitted to a rotational consolidation regimen lasting 6 months. When no HLA-identical donor was available, patients aged <55 years underwent stem cell harvest followed by autologous transplantation; patients aged >/=55 years received standard maintenance treatment for 6 months. In the second year, maintenance treatment (all ages) was based on cycles of alpha-IFN (3 MU three times a week for 6 weeks) alternated with methotrexate/6-mercaptopurine continuously for up to 2 years from first demonstration of CR. Thereafter, patients maintaining CR had the same schedule of alpha-IFN (6 weeks on, 6 off). Eight patients (6/8 first diagnosis, 2/2 relapsed) obtained morphological, immunological and cytogenetic CR with persistent molecular positivity. Two with an HLA-identical donor had allogeneic bone marrow transplantation. Six proceeded with chemotherapy: one experienced early relapse, three were autotransplanted, and two received maintenance. Five patients then received alpha-IFN as scheduled. All five are in continuous morphological and cytogenetic CR, with a longer mean duration of maintained morphological CR (mean 46 months; range: 20-88) than in previous reports of Ph+ ALL patients treated with chemotherapy regimens (excluding allogeneic BMT). alpha-IFN thus appears effective in this poor-risk subset of patients. This well-tolerated IFN-containing maintenance treatment could be considered to reinforce intensified programs based on autologous stem cell transplantation as an alternative to allogeneic transplantation in P190BCR-ABL+ ALL patients (and by extension for Ph+ ALL patients) lacking an HLA-matched donor. Leukemia (2000) 14, 22-27.
Assuntos
Proteínas de Fusão bcr-abl/genética , Interferon-alfa/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Indução de Remissão , Análise de Sobrevida , Adulto , Idoso , Transplante de Medula Óssea , Terapia Combinada , Transplante de Células-Tronco Hematopoéticas , Humanos , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Resultado do TratamentoRESUMO
Flow cytometric expression of bcl-2 protein was analyzed in 90 newly diagnosed acute myeloblastic leukemia (AML) patients using an anti-bcl-2 monoclonal antibody by direct immunofluorescence technique and results were correlated with FAB cytotype, CD34 expression and clinical outcome. Bcl-2 was expressed in all AML cases with different intensity. The mean fluorescence index (MFI), expressed as the ratio of sample mean channel:control mean channel, ranged from 3.0 to 39.5 with a median value of 14. The MFI was significantly higher (P = 0.01) in M0 (20.9) and M1 (18.3) than in M2 (11.7), M3 (12.4), M4 (11.8) and M5 (9.5) cytotypes. In addition, bcl-2 MFI significantly correlated both with CD34 positivity (P = 0.001) and with CD34 MFI (P = 0.01), being CD34 antigen expressed in 65% of patients with a bcl-2 MFI >14, and only in 35% of AML cases with a bcl-2 MFI >14. When bcl-2 intensity expression was correlated with complete remission (CR) rate, a higher MFI was associated with a low CR rate after standard intensive chemotherapy. In particular, CR was achieved in 86% of patients with a bcl-2 MFI <14, but only in 57% of patients with a MFI >14 (P = 0.008). A further decrease of CR rate to 41% was observed in patients in whom a higher bcl-2 MFI was coupled with the presence of CD34 antigen on their blasts. By statistical analysis we also demonstrated that both bcl-2 high MFI (>14) and CD34 expression are independent prognostic factors for achieving CR in AML. These data raise the hypothesis that high values of bcl-2 may confer on myeloid blasts a higher resistance to standard chemotherapy. However, identification of patients with high expression of bcl-2 may be important for a different therapeutic approach.
Assuntos
Antígenos CD34/análise , Leucemia Mieloide Aguda/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Since according to the early studies, the outcome after splenectomy in the individual patient with myelofibrosis with myeloid metaplasia (MMM) is unpredictable, we assessed retrospectively the pre-intervention characteristics that best predicted adverse events, hematological consequences, and survival in 71 splenectomized MMM patients. The findings indicate that the operative risk of splenectomy for both mortality (8.4%) and morbidity (39.3%) was unpredictable. New hemorrhagic or thrombotic complications occurred in 16.9% of surviving patients and were predicted by age < 50 years, a normal to high platelet count (> 200 x 10(9)/l) and huge splenomegaly (> 16 cm from the costal margin). Massive liver enlargement occurred in 24% of patients and has to be expected in patients splenectomized for transfusion-dependent anemia. Anemia improved substantially in 45% and 52% of patients at 3 months and at 1 year, respectively, and was predicted by severe anemia, low platelet count (< 100 x 10(9)/l) or normal to high white blood cell (WBC) count (> 4 x 10(9)/l). Survival from splenectomy was superior in patients < 45 years with WBC < 10 x 10(9)/l count. An unexpectedly high rate of blastic transformation was observed. It accounted for 42.8% of the deaths. The results suggest trials for prophylactic cytoreductive treatment in young patients and when platelet count is normal to increased. Further study is needed for elucidating the possible role played by splenectomy in inducing blastic transformation.
Assuntos
Anemia/cirurgia , Mielofibrose Primária/cirurgia , Baço/patologia , Esplenectomia , Adulto , Idoso , Anemia/sangue , Anemia/etiologia , Anemia/mortalidade , Transfusão de Sangue , Feminino , Hemoglobina A/metabolismo , Hemorragia/etiologia , Hepatomegalia/etiologia , Humanos , Contagem de Leucócitos , Masculino , Metaplasia/sangue , Metaplasia/mortalidade , Metaplasia/cirurgia , Pessoa de Meia-Idade , Contagem de Plaquetas , Mielofibrose Primária/sangue , Mielofibrose Primária/mortalidade , Esplenectomia/efeitos adversos , Esplenectomia/mortalidade , Análise de Sobrevida , Trombose/etiologiaRESUMO
PSC 833 (Valspodar) can reverse multidrug resistance (MDR) in patients with hematologic malignancies, but alters the pharmacokinetics of concomitant anticancer agents. A phase I, dose-finding study was initiated to define a safe and effective regimen of mitoxantrone, etoposide, and cytarabine (MEC) when administered with PSC 833 to patients with early relapsed or refractory acute myeloid leukemia (AML). Poor-prognosis AML patients refractory to first-line induction therapy or relapsing within 9 months of attaining complete remission (CR) were treated with cytarabine (1.0 g/m2/day), etoposide (30 mg/m2/day), and mitoxantrone at a dose of either 3.0 mg/m2/day (cohort 1) or 4.5 mg/m2/day (cohorts 2 and 3) for 6 days plus continuous-infusion PSC 833 (10 mg/kg/24 h with a 2.0 mg/kg loading dose) for 6 or 7 days each 21-day cycle. Patients achieving CR were given a 4-day MEC plus PSC 833 consolidation cycle. Twenty-three patients were enrolled (eight with primary refractory AML and 15 in relapse). Dose-limiting toxicity occurred in one of six patients in cohort 2 (grade 4 mucositis) and one of seven patients in cohort 3 (grade 4 hyperbilirubinemia). The maximum tolerated dose of mitoxantrone was defined as 4.5 mg/m2/day. Clinically significant grade 4 hyperbilirubinemia, possibly related to PSC 833, occurred in four patients. Hematologic toxicities were as expected in this patient population, but were not dose limiting. Mild to moderate cerebellar ataxia and paresthesia occurred in six (26%) and five (22%) patients, respectively, but were not dose limiting. Overall, six of 23 (26%) patients achieved CR, including five patients with demonstrated P-glycoprotein expression and/or function. The median overall survival was 4 months. All six patients with a CR were alive and four (17%) patients were disease free at 12 months. Blood levels of PSC 833 were well above the target level of 1000 ng/ml, a concentration that is known to reverse MDR in vitro. PSC 833 reduced the clearance of etoposide by approximately two-fold. No correlation was observed between the mitoxantrone or etoposide area under the curve and response. In conclusion, the MEC plus PSC 833 tested regimen was well tolerated and the 26% CR rate warrants further testing of this regimen in a randomized, phase III trial.