RESUMO
In chronic-phase chronic myeloid leukaemia (CP-CML), residual BCR-ABL1+ leukaemia stem cells are responsible for disease persistence despite TKI. Based on in vitro data, CHOICES (CHlorOquine and Imatinib Combination to Eliminate Stem cells) was an international, randomised phase II trial designed to study the safety and efficacy of imatinib (IM) and hydroxychloroquine (HCQ) compared with IM alone in CP-CML patients in major cytogenetic remission with residual disease detectable by qPCR. Sixty-two patients were randomly assigned to either arm. Treatment 'successes' was the primary end point, defined as ≥0.5 log reduction in 12-month qPCR level from trial entry. Selected secondary study end points were 24-month treatment 'successes', molecular response and progression at 12 and 24 months, comparison of IM levels, and achievement of blood HCQ levels >2000 ng/ml. At 12 months, there was no difference in 'success' rate (p = 0.58); MMR was achieved in 80% (IM) vs 92% (IM/HCQ) (p = 0.21). At 24 months, the 'success' rate was 20.8% higher with IM/HCQ (p = 0.059). No patients progressed. Seventeen serious adverse events, including four serious adverse reactions, were reported; diarrhoea occurred more frequently with combination. IM/HCQ is tolerable in CP-CML, with modest improvement in qPCR levels at 12 and 24 months, suggesting autophagy inhibition maybe of clinical value in CP-CML.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Análise Citogenética/métodos , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Idoso , Feminino , Seguimentos , Humanos , Hidroxicloroquina/administração & dosagem , Mesilato de Imatinib/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
After failure of erythropoiesis-stimulating agents (ESAs), lenalidomide (LEN) yields red blood cell (RBC) transfusion independence (TI) in 20-30% of lower-risk non-del5q myelodysplastic syndrome (MDS). Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement six RBC units per 8 weeks) lower-risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg per day, 21 days per 4 weeks (L arm) or LEN (same schedule) + erythropoietin (EPO) beta, 60,000 U per week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after four treatment cycles (primary end point) was 23.1% (95% CI 13.5-35.2) in the L arm and 39.4% (95% CI 27.6-52.2) in the LE arm (P=0.044), while RBC-TI was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the two arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower-risk non-del5q MDS patients with anemia resistant to ESA.
Assuntos
Transfusão de Sangue , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Eritropoetina/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Talidomida/análogos & derivados , Idoso , Anemia/prevenção & controle , Inibidores da Angiogênese/uso terapêutico , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Fatores de Risco , Talidomida/uso terapêuticoRESUMO
PURPOSE: A small proportion of patients with chronic myeloid leukemia (CML) achieve a complete cytogenetic response (CCR), defined as the disappearance of Philadelphia (Ph) chromosome-positive metaphases, after treatment with interferon alfa (IFN). In this population of patients, the question of whether treatment should then be withdrawn is not yet resolved. PATIENTS AND METHODS: In the present study, we followed 15 patients who stopped IFN after achieving CCR. In nine patients IFN was stopped in view of adverse reactions (n = 8) or patient's choice (n = 1). For the remaining six patients, the treatment was stopped because no BCR/ABL rearrangement could be detected by reverse transcriptase polymerase chain reaction (RT-PCR) in four successive analyses using peripheral-blood samples. RESULTS: Loss of CCR and survival were not statistically different (P =.48; P =.7) for the 15 patients who stopped IFN compared with 41 other CCR patients who continued IFN therapy in our institution. The median follow-up after discontinuation of IFN treatment was 36 months (range, 6 to 108 months). Seven patients (47%) (females, or CCR > 24 months and RT-PCR negative before IFN cessation; P <.0001) did not relapse. Eight other patients (53%) relapsed (lost CCR) within 3 to 33 months of treatment discontinuation. One of them relapsed in major cytogenetic remission (MCR) and was still in MCR 87 months after stopping therapy without any treatment. CONCLUSION: It is possible to stop IFN treatment at least in some patients with CML who achieve a prolonged period of CCR. This study also illustrates the hypothesis that persistence of low numbers of Ph-positive cells does not necessarily imply hematologic relapse.
Assuntos
Antineoplásicos/administração & dosagem , Interferon-alfa/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/sangue , Proteínas de Fusão bcr-abl/genética , Humanos , Interferon-alfa/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Fatores de Risco , Estatísticas não Paramétricas , Taxa de Sobrevida , Fatores de TempoRESUMO
PURPOSE: The aims of the current study were to evaluate in patients with high-risk multiple myeloma (MM) the feasibility and usefulness of high-dose chemotherapy or chemoradiotherapy followed by hematopoietic stem-cell support with autologous peripheral-blood progenitor cells (PBPC) harvested after high-dose cyclophosphamide (HDCYC). PATIENTS AND METHODS: Seventy-three patients with high-risk MM were entered onto the study. Before the procedure, all patients had received HDCYC to collect PBPC by leukapheresis. One patient died of infection after HDCYC. All other patients subsequently received high-dose melphalan (HDM) (140 mg/m2) either alone (n = 1) or associated with either busulfan (16 mg/kg; n = 4) or total-body irradiation (TBI) (8 to 15 Gy; n= 67). In addition, three of the latter patients received cyclophosphamide (120 mg/kg). Thereafter, PBPC were reinfused either alone in 61 patients or together with back-up bone marrow cells in 11 patients in whom the granulocyte-macrophage colony-forming unit (CFU-GM) cell content of the leukapheresis was low. RESULTS: One patient died of acute cardiac failure after reinfusion of PBPC; three patients did not respond after autologous blood progenitor cell transplantation (ABPCT), while the other 68 patients achieved either a complete response (CR; n = 32) or partial response (PR; n = 36). Thirty-six patients relapsed or progressed after a median response duration of 14.5 months (range, 3 to 43) and 19 of these subsequently died. Four other patients died while still responsive of lung cancer (n = 1) or infection (n = 3). The remaining 28 patients are currently alive and still responding with a median follow-up duration of 27 months (range, 6 to 66). The 3-year probability of survival was 66% +/- 12% (95% confidence interval [CI] after ABPCT and 77% +/- 51% (95% CI) from diagnosis. CONCLUSION: High-dose chemotherapy or chemoradiotherapy followed by autologous PBPC support in MM is feasible and efficient. Further studies are needed to confirm these encouraging, although preliminary, results and to compare this technique with other therapeutic strategies.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/cirurgia , Adulto , Idoso , Análise de Variância , Bussulfano/administração & dosagem , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Estudos de Viabilidade , Feminino , Humanos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/radioterapia , Prognóstico , Modelos de Riscos Proporcionais , Dosagem Radioterapêutica , Radioterapia Adjuvante , Fatores de Risco , Análise de Sobrevida , Transplante Autólogo , Resultado do TratamentoRESUMO
The leukemogenic property of BCR-ABL in chronic myeloid leukemia (CML) is critically dependent on its protein tyrosine kinase activity. STI571 inhibits the BCR-ABL kinase activity, the growth and the viability of BCR-ABL expressing cells. In this study, we report the apoptotic effect of STI571 in combination with daunorubicin (DNR) on peripheral blood mononuclear cells from 11 CML patients and four BCR-ABL-positive cell lines: AR230, LAMA84, K562 and KCL22. Primary blast cells were identified by flow cytometry on the basis of their low CD45 expression. Nucleus fragmentation, exposure of phosphatidylserines and decrease in mitochondrial membrane potential were measured using acridine orange, FITC-annexin V and DiOC6(3), respectively, to evaluate apoptosis. On cell lines, the effect of DNR was negligible, whereas STI571 induced 10 to 35% of apoptosis in 18 h. STI571 sensitized AR230, LAMA84 and K562 cells to DNR when apoptosis was measured at the mitochondrial and membrane but not the nuclear levels. On CML blast cells, phosphatidyl serine exposure was significantly induced by both DNR and STI571 and was higher when these drugs were used in combination (P < 0.0003). However, the effects of this drug combination were only additive and no sensitization of blast cells to DNR by STI571 was observed. Interestingly, sensitization was evidenced in CML but not normal lymphocytes. These results suggest that other mechanisms additional to Bcr-Abl tyrosine kinase activity could be responsible for DNR resistance, and further investigations are needed to understand its origin.
Assuntos
Antineoplásicos/farmacologia , Apoptose , Daunorrubicina/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/farmacologia , Pirimidinas/farmacologia , Benzamidas , Núcleo Celular/ultraestrutura , Fragmentação do DNA , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/farmacologia , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Fosfatidilserinas/análise , Células Tumorais CultivadasRESUMO
To improve the management of chronic myeloid leukemia (CML) in a single center, we used interferon alpha (IFN alpha) to treat newly diagnosed CML patients and investigated the factors predictive of a major cytogenetic response. Fifty-two patients (pts) with a median age of 51.5 years (16-68), were given interferon alpha (IFN alpha) (5 millions/m2/day, subcutaneously). The median interval between diagnosis and IFN alpha was 41.5 days (0-160). The doses of INF alpha were adjusted to maintain the white blood cell (WBC) count between 1.5 and 5 x 10(9)/l and the platelet count between 50 and 100 x 10(9)/l. At diagnosis, Sokal's criteria were used to classify patients into three groups: low (n = 24), intermediate (n = 19) and high risk (n = 9). A complete hematological response (CHR) was achieved in 42 cases (80.7%). A partial response was present in nine; only one patient did not respond. By multivariate logistic regression analysis, only the age at diagnosis was found to influence the CHR rate (P = 0.06). Cytogenetic response was evaluated in 46 responder patients. Twenty-three patients achieved a major cytogenetic response (MCR) which was either partial ( > or = 65% pH negative cells) (n = 3) or complete (CCR) (n = 20). By univariate analysis, two disease-related variables were found to influence the MCR rate in 40 evaluable CHR patients: spleen size at diagnosis and peripheral blood blast percentage. However, using either univariate or multivariate analysis, the most significant factor was the achievement of CHR within 3 months (P < 0.0004 and P < 0.0002, respectively). These results show that IFN alpha can induce high rates of hematological and cytogenetic responses when administered in doses leading to myelosuppression. The achievement of CHR within 3 months could be useful to identify early, those patients who will not respond to IFN alpha and who need alternative treatments such as allogeneic or autologous stem cell transplantation.
Assuntos
Interferon Tipo I/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Adolescente , Adulto , Idoso , Feminino , Humanos , Injeções Subcutâneas , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Cromossomo Filadélfia , Valor Preditivo dos Testes , Proteínas Recombinantes , Análise de Regressão , Análise de SobrevidaRESUMO
Autografting could become a promising treatment for patients with chronic myeloid leukemia (CML) who cannot undergo allogeneic bone marrow transplantation or failed to respond to recombinant alpha-interferon (IFN). In this review, we analyze the results which have been published for patients transplanted in chronic phase and which suggest that autografting could prolong survival, at least in some patients. We also discuss the different methods of purging whose clinical efficacy remains to be assessed.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide de Fase Crônica/terapia , Purging da Medula Óssea/métodos , Humanos , Interferon gama/uso terapêutico , Leucemia Mieloide de Fase Crônica/mortalidade , Taxa de Sobrevida , Transplante AutólogoRESUMO
Acute lymphoblastic leukemia (ALL) in the elderly is characterized by its poor prognosis. Forty patients with ALL, aged 55 years or older, and with good performance status (ECOG <3) were prospectively treated according to an age-adapted regimen: induction therapy was derived from the LALA87 protocol while the feasibility of treatment with interferon combined with chemotherapy was assessed during maintenance. Compared with younger adults treated according to the LALA87 protocol, elderly patients did not present with more adverse prognostic features, except for a lower incidence of T cell ALL (9 vs 31%, P=0.005). There were even less patients with a high leukocyte count (15 vs 38%, P=0.003), a characteristic associated with adverse prognosis while the incidence of Philadelphia-positive (Ph-positive) ALL was not significantly increased compared to younger adults (31 vs 20%, P=0.2). After completion of induction therapy, with or without salvage treatment, 85% (CI: 70-94%) obtained a complete response (CR) while treatment-related mortality during induction was 7.5% (CI: 2-20%). Median overall survival and disease-free survival were 14.3 months and 14 months, respectively, which, although inferior to results achieved in younger adults, compares favorably with available data in the elderly. Treatment with IFN proved feasible in most patients but had to be discontinued in eight patients because of toxicity. Age-adapted treatment improves the prognosis of ALL in the elderly even if, in most cases, a cure cannot be achieved.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Interferons/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Idoso , Ciclofosfamida , Daunorrubicina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Estudos Prospectivos , Esteroides , VincristinaRESUMO
The aim of the study was to analyze the factors influencing peripheral blood progenitor cell (PBPC) collection after high-dose cyclophosphamide (HDCYC) (7 g/m2) and hematopoietic recovery after autologous transplantation of HDCYC-mobilized PBPC (ABPCT) in 116 patients with aggressive multiple myeloma (MM). Following HDCYC 74 patients received hematopoietic growth factors (HGF), either G-CSF (n = 19) or GM-CSF (n = 55). All the patients were subsequently planned to undergo ABPCT. PBPC collection was possible for 106 patients. The most important prognostic factor for collection of more than 25 x 10(4) CFU-GM cells/kg and 2 x 10(6) CD34+ cells/kg was the use of HGF (P = 0.002 and 0.009, respectively). Previous use of an alkylating agent, response to treatment before HDCYC, and interval between diagnosis and HDCYC were also significant factors (P = 0.004, 0.025 and 0.001, respectively). The number of CFU-GM cells infused was the most important parameter for rapid and complete hematological recovery after ABPCT (P < 0.0001). Thus the use of HGF post-HDCYC is the major factor which, associated with reduced time between diagnosis and HDCYC and the use of an alkylating agent, could increase the numbers of hematopoietic progenitors collected, and subsequently improve hematopoietic recovery following ABPCT in MM patients.
Assuntos
Antineoplásicos/administração & dosagem , Ciclofosfamida/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/sangue , Mieloma Múltiplo/terapia , Adulto , Idoso , Análise de Variância , Feminino , Humanos , Leucaférese , Masculino , Pessoa de Meia-Idade , Transplante AutólogoRESUMO
In 204 adult patients with de novo acute myeloid leukemia (AML), we prospectively compared allogeneic bone marrow transplantation (alloBMT), autologous stem cell transplantation (ASCT) and chemotherapy (Chemo). 162 patients (79.4%) achieved a complete remission (CR). Of the 135 patients who were still in CR after consolidation, 96 patients were less than 46 years of age: 36 patients had an HLA-identical sibling donor and were allocated for alloBMT (group I); they were compared to the 60 other patients who did not have an HLA-identical sibling donor and were treated with either ASCT or chemotherapy (group II). The 3-year disease-free survival was higher for group I patients (66.5 +/- 16%) than for the 60 group II patients (42.4 +/- 13%) (P < 0.05). The actuarial risk of relapse at 3 years was significantly lower for group I patients (24 +/- 15%) than for the other 60 group II patients (56 +/- 13%; P < 0.009). By multivariate analysis, the disease-free survival and risk of relapse were influenced by the initial WBC count (P < 0.02 and P < 0.006), the number of chemotherapy courses for CR (P < 0.001 and P < 0.01) and the type of post-induction treatment (alloBMT vs no alloBMT; P < 0.1 and P < 0.02). The 99 patients who did not fulfill the inclusion criteria for alloBMT were given intensive chemotherapy including high-dose aracytine. When they were still in CR (n = 77), these patients were then randomized for either ASCT (n = 39) or Chemo (n = 38). We were unable to detect any statistical difference between ASCT and Chemo for either disease-free survival, risk of relapse or survival. These results indicate that alloBMT seems to produce results which are at least superior to those of other therapeutic modalities. The results of either ASCT or Chemo look similar.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/cirurgia , Doença Aguda , Adolescente , Adulto , Terapia Combinada , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de RemissãoRESUMO
The EMA86 study showed efficacy of intensive sequential chemotherapy with mitoxantrone, 12 mg/m2 day on days 1-3, etoposide, 200 mg/m2/day as a continuous infusion on days 8-10 and cytarabine (araC), 500 mg/m2/day as continuous infusion on days 1-3 and 8-10 (EMA regimen) in previously treated patients with AML. The goal of the EMA91 study was to determine whether administration of GM-CSF between the two sequences of EMA chemotherapy and during the second sequence could increase therapeutic efficacy by potentially increasing leukemic cell recruitment into the S phase of cell cycle before the second sequence. One hundred and ninety-two patients aged less than 65 years with previously treated AML received GM-CSF, 5 microg/kg/day or placebo from day 4 to day 8 of EMA chemotherapy. One hundred and twenty were refractory and 72 were in first relapse after a complete remission (CR) of more than 6 months duration. CR rates after one course of chemotherapy were 65% in the GM-CSF group (refractory: 51%; first relapse: 89%), not significantly different from the 59% CR rate (refractory: 46%; first relapse: 81%) in the placebo group. Median time to recovery of neutrophils was 38 and 37 days and median time to last platelet transfusion 32 and 32 days respectively in the GM-CSF and placebo groups. WHO grade > or = 3 non-hematologic toxicities were mainly sepsis (45% and 51%, respectively) and mucositis (34% and 31%) and did not differ between the two groups. Toxic death rate was 5% and 8%, respectively, in the GM-CSF and placebo groups. Patients achieving CR were scheduled to receive six courses of maintenance with reduced-dose EMA. Time to progression tended to be longer in the GM-CSF group (median 154 vs 115 days, progression-free rate at 18 months 33% vs 19%, P = 0.08), particularly in refractory patients (P = 0.06). However, at the current follow-up, this did not translate into a significantly longer disease-free survival and survival. Cell cycle studies showed increased recruitment of cells in the S phase between day 4 and day 8 in the GM-CSF group compared to placebo (P = 0.006). However, this did not significantly relate to prognosis in this cohort of patients. GM-CSF might marginally increase efficacy of sequential chemotherapy without increasing its toxicity in the absence of any detected relationship between this effect and observed leukemic cell recruitment into the cell cycle.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Leucemia Mieloide/tratamento farmacológico , Doença Aguda , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Divisão Celular/efeitos dos fármacos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Intervalo Livre de Doença , Sinergismo Farmacológico , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Hematopoese/efeitos dos fármacos , Humanos , Leucemia Mieloide/patologia , Leucemia Mieloide/fisiopatologia , Masculino , Mitoxantrona/administração & dosagem , Mitoxantrona/efeitos adversos , RecidivaRESUMO
The rate of relapse after allogeneic bone marrow transplantation (BMT) varies between 15 and 60%. New therapeutic strategies are required urgently as no significant results have been obtained with standard chemotherapy. The best results of second allogeneic BMT have been obtained when the interval between the first and the second transplant was more than 6 to 20 months, depending on the study. Veno-occlusive disease was an important cause of non-leukemic death (13-65%). As the toxicity of second BMT is very high, other treatments have been considered: complete remissions were reported after sudden discontinuation of the immunosuppressive therapy. Interferon-alpha has been used for chronic myeloid leukemia patients and may achieve hematological and cytogenetic complete remission. More recently, donor leucocytes transfusions have been proposed and at least in some cases, have led to molecular complete remission (polymerase chain reaction with double amplification) in chronic myeloid leukemia patients. However, non predictable marrow aplasias and graft-versus-host reactions hamper the efficacy of this strategy. Finally, hemopoietic growth factors used to promote donor cell growth produce interesting results which deserve further studies.
Assuntos
Transplante de Medula Óssea , Leucemia/terapia , Linfoma/terapia , Terapia de Salvação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Intervalo Livre de Doença , Doença Enxerto-Hospedeiro , Fatores de Crescimento de Células Hematopoéticas/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Interferon-alfa/uso terapêutico , Leucemia/mortalidade , Transfusão de Leucócitos , Linfoma/mortalidade , Prognóstico , Indução de Remissão , Reoperação , Falha de TratamentoRESUMO
Twenty-three patients with acute myelogenous leukemia (AML) in first relapse were treated with high-dose cytosine-arabinoside (Ara-C) and amsacrine or idarubicin. To prime the cells, the patients were given rhGM-CSF. We studied the influence of 48-h infusion of rhGM-CSF on proliferation and Ara-C sensitivity of leukemic cells both ex vivo and in vitro. We found that a 48-h infusion of rhGM-CSF increased both white blood cell counts and peripheral blood blast cell percentages. Using a Bromodeoxyuridine/DNA (BrdUrd/DNA) staining in flow cytometry, we found an non-constant increase in cells in the S-phase. Ex vivo 48-h culture of leukemic cells with or without rhGM-CSF, with or without other hematopoietic growth factors (HGFs), showed a greater increase of the cells in the S-phase with GF but no correlation with the ex vivo results. We used a method of quantitation of the DNA synthesis previously described (Lacombe F., et al. (1992) Cytometry 13, 730) to monitor the Ara-C sensitivity of the cells in S-phase before and after 48-h infusion with rhGM-CSF. We observed a great variation in the Ara-C sensitivity of the leukemic cells before and after infusion with rhGM-CSF from one patient to another. The BrdUrd/DNA method seems a convenient method to study the influence of HGFs on Ara-C sensitivity of the patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Leucemia Mieloide/tratamento farmacológico , Doença Aguda , Adolescente , Adulto , Idoso , Bromodesoxiuridina/análise , Ciclo Celular , Citarabina/administração & dosagem , DNA de Neoplasias/análise , Relação Dose-Resposta a Droga , Interações Medicamentosas , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Citometria de Fluxo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Humanos , Leucemia Mieloide/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Recombinantes/administração & dosagem , Fase S/efeitos dos fármacosRESUMO
By using flow cytometry, the intracellular accumulation (Acc) of idarubicin (IDA) and daunorubicin (DNR) and the effect of verapamil (VRP) on both anthracycline accumulation (VRP index) were studied in leukemic cell lines (K562 and HL60 and their two DNR-resistant subclones) and fresh leukemic cells. IDA accumulated more than DNR in both parental (K562: p < 0.03 and HL60: 0.09) and resistant cell lines (p < 0.01 for both cell lines) irrespective of whether or not they were treated with VRP. VRP index was higher for DNR than for IDA (p < 0.05). Similar results were observed in fresh leukemic blasts from 25 patients with ANLL (IDA Acc superior to DNR Acc: p < 0.0001; higher VRP index for DNR than for IDA: p < 0.01). The higher Acc of IDA than DNR seen in fresh leukemic cells could explain the better clinical efficacy of IDA reported in patients with ANLL.
Assuntos
Daunorrubicina/farmacocinética , Idarubicina/farmacocinética , Leucemia Mieloide Aguda/metabolismo , Verapamil/farmacologia , Adolescente , Adulto , Resistência a Medicamentos , Feminino , Citometria de Fluxo , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Células Tumorais CultivadasRESUMO
In our institution, total body irradiation (TBI) is performed by means of a sweeping beam technique. Toxicity of the procedure was evaluated according to the only grading system designed for high dose chemoradiotherapy. One hundred patients undergoing TBI and conditioned with a standard cyclophosphamide regimen before BMT were evaluated. Regimen-related toxicity was graded according to the Seattle transplantation toxicity system, from 0 to IV (fatal toxicity), in eight organs on days 0, 7, 14, 28 and 100 for lungs. Eighteen patients did not develop any toxicity. Grades III, IV toxicities were uncommon (9%) and were not influenced by dose of TBI, GVHD prophylaxis, disease status and allogenicity although no grade IV toxicity was observed among autologous marrow recipients. However, grade II toxicity was more common in patients receiving allogeneic vs autologous grafts (p < 0.01) because of increased mucosal (p = 0.002) and liver (p = 0.12) toxicities. Renal toxicity was unevaluable. When cumulative toxicity was equal or higher than 4, day 100 survival was worse (p = 0.05). These data confirm the safety of our TBI procedure and the validity of the grading system except for renal toxicity. We suggest that a more aggressive conditioning regimen may be tolerated by patients receiving autologous grafts.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Irradiação Corporal Total/efeitos adversos , Adolescente , Adulto , Transplante de Medula Óssea/mortalidade , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Taxa de Sobrevida , Fatores de Tempo , Irradiação Corporal Total/métodos , Irradiação Corporal Total/mortalidadeRESUMO
We report our experience with 67 patients with myeloid malignancies (acute myeloid leukaemia (AML) or chronic myelogenous leukaemia (CML) conditioned with busulphan and melphalan as preparation for autologous haemopoietic cell transplantation. The major non-haematological toxicities were severe mucositis, nausea and vomiting, but the marrow aplasia was delayed and of short duration. The anti-tumor effect was appreciable with subsequent chronic phase (CP) obtained in 30/31 CML in transformation and complete remission (CR) obtained in 2/3 refractory AML. Among 32 patients treated while they had no evidence of active disease, 12 remained in CR or CP with a median follow-up of 54.7 months.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mieloide/terapia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Terapia Combinada , Feminino , Humanos , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-IdadeRESUMO
High-dose cyclophosphamide (HD-CY; 7 g/m2) was administered to patients suffering from high risk multiple myeloma (MM). The safety of this procedure, the recirculation and collection of peripheral blood stem cells (PBSC) and the effect of rhGM-CSF and HD-CY were studied. Group I patients (n = 21) were treated with HD-CY alone. Group II patients (n = 10) received 5 micrograms/kg/day rhGM-CSF iv after HD-CY. Neutropenia was shorter in group II (p = 0.01). In group II, the number of circulating colony forming units (CFU-GM) after 14 days was correlated with the number of circulating CFU-GM after 7 days (r = 0.85, p < 0.0001) and with the number of CD34+ cells (r = 0.839, p = 0.01). The total number of mononuclear cells (MNC) and CFU-GM collected per patient was two and seven-fold higher, respectively, in group II (p = 0.01 and p = 0.03). Recovered MNC and CFU-GM were 1.7 and 7-fold higher, respectively, in group II (p = 0.01 and p = 0.004). Our data show that HD-CY is an efficient means of collecting functional PBSC in MM. We suggest that rhGM-CSF is able to further enhance this yield in MM.
Assuntos
Transplante de Medula Óssea/métodos , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/cirurgia , Adulto , Separação Celular/métodos , Ensaio de Unidades Formadoras de Colônias , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Hematopoese , Células-Tronco Hematopoéticas/patologia , Humanos , Leucaférese , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/tratamento farmacológico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversosRESUMO
Umbilical cord blood (UCB) cells from HLA-matched donors are used as an alternative to bone marrow for allogeneic transplantation and reports of successful UCB transplantation in patients with severe aplastic anemia (SAA) are scarce. SAA was discovered in a 4-year-old girl in February 1990. Transfusion support started in August 1990 and standard treatments were unsuccessful. The birth of an HLA-compatible brother in October 1993 permitted the cryopreservation of UCB. In December 1994 UCB transplantation was decided upon. No toxicity occurred. G-CSF was started at day 28. WBC and PMN reached 0.5 x 10(9)/l at days 33 and 37. RBC and platelet transfusion independence were reached at days 50 and 52. Mixed chimerism was demonstrated in blood cells at 1.5, 4 and 6 months after UCBT by molecular biology (VNTR). FISH studies yielded similar results at 15 and 18 months. Twenty months after UCBT, molecular biology showed full donor chimerism. Clinical follow-up (last follow-up: 32 months post transplant) is unremarkable. We suggest that CY and ATG may be a suitable regimen for related HLA-compatible UCBT in patients with SAA. Residual recipient cells can disappear even very late after UCBT, permitting the establishment of complete donor chimerism.
Assuntos
Anemia Aplástica/terapia , Transplante de Células-Tronco Hematopoéticas , Pré-Escolar , Feminino , Sangue Fetal , Sobrevivência de Enxerto , Humanos , Quimeras de Transplante , Transplante HomólogoRESUMO
High-dose cyclophosphamide (HDC) has been shown to be an effective regimen for collecting PBPC in multiple myeloma (MM) patients, but the optimal dose to be used remains controversial. Two historical cohorts of MM patients who received G- or GM-CSF and HDC at the dose of either 7 g/m(2) (HDC7, n = 74) or 4 g/m (HDC4, n = 42) were compared. As patients in the HDC4 group were more likely to have received G-CSF than GM-CSF (P < 10(-3)) and fewer previous alkylating agents (P = 0.004), multivariate logistic regression analysis was performed. In the HDC4 group, patients had a shorter median duration of neutropenia (P < 10(-4)), fewer RBC (P < 10(-3)) and platelet transfusions (P < 10(-3)) with fewer patients with platelets <20 x 10(9)/l (P = 0.004). Moreover, fewer febrile episodes (P < 10(-3)) and less need of intravenous antibiotics (P < 10(-3)) were found in the HDC4 group. No statistical difference was observed with regard to CD34(+) cell collection efficiency. Thus, the use of HDC at the dose of 4 g/m(2) for the collection of PBPC in MM patients decreases hematological and extrahematological toxicity with an equivalent CD34(+) cell collection efficiency.
Assuntos
Ciclofosfamida/administração & dosagem , Ciclofosfamida/toxicidade , Mobilização de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Adulto , Idoso , Antígenos CD34 , Estudos de Coortes , Sobrevivência de Enxerto , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucaférese , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Fatores de TempoRESUMO
We retrospectively analysed the factors that influenced rate of haemopoietic recovery (HR) in 243 patients after transplantation with chemotherapy-mobilised autologous peripheral blood progenitor cells (PBPC). Approximately half the patients also received haemopoietic growth factors (HGF) for mobilisation. Conditioning for transplantation was with either chemotherapy alone or chemotherapy plus total body irradiation (TBI). Median time to recovery of granulocytes > or = 0.5 x 10(9)/l was 13 days (range 7-93 days) and of platelets > or = 50 x 10(9)/l 14 days (7-440). Speed of HR was greater, both for neutrophils and platelets for patients who received more rather than less CFU-GM than our median value of 18.9 x 10(4)/kg (P < 0.0001 in both instances) and more rather than less CD34-positive cells than our median value of 8.8 x 10(6)/kg (P < 0.0001 and P < 0.0005, respectively). For granulocyte recovery, in the multivariate analysis the dose of infused CFU-GM (P = 0.05) and the use of HGF for both mobilisation and post-transplantation (P < 0.0014) were significant positive factors. For platelet recovery in the multivariate analysis the dose of infused CFU-GM (P < 0.0016) was a positive factor. The use of busulphan and of TBI were significant adverse factors for rate of platelet recovery (P = 0.005 and 0.0004, respectively). When compared with non-HGF-mobilised PBPC, HGF-mobilised PBPC reduced the number of days of hospitalisation (28 vs 24, P = 0.0001) and of treatment with intravenous antibiotics (15 vs 11, P = 0.0004). These findings emphasise the importance of cell dose in accelerating haemopoietic recovery after autologous blood stem cell transplantation.