RESUMO
Although high-dose therapy and autologous stem cell transplant (ASCT) is superior to conventional chemotherapy for treatment of myeloma, most patients relapse and the time to relapse depends upon the initial prognostic factors. The administration of non-cross-resistant chemotherapies during the post-transplant period may delay or prevent relapse. We prospectively studied the role of consolidation chemotherapy (CC) after single autologous peripheral blood stem cell transplant (auto-PBSCT) in 103 mostly newly diagnosed myeloma patients (67 patients were < or =6 months from the initial treatment). Patients received conditioning with BCNU, melphalan+/-gemcitabine and auto-PBSCT followed by two cycles of the DCEP+/-G regimen (dexamethasone, cyclophosphamide, etoposide, cisplatin+/-gemcitabine) at 3 and 9 months post-transplant and alternating with two cycles of DPP regimen (dexamethasone, cisplatin, paclitaxel) at 6 and 12 months post-transplant. With a median follow-up of 61.2 months, the median event-free survival (EFS) and overall survival (OS) are 26 and 54.1 months, respectively. The 5-year EFS and OS are 23.1 and 42.5%, respectively. Overall, 51 (49.5%) patients finished all CC, suggesting that a major limitation of this approach is an inability to deliver all planned treatments. In order to improve results following autotransplantation, novel agents or immunologic approaches should be studied in the post-transplant setting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/terapia , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante , Adulto , Idoso , Cisplatino , Terapia Combinada/métodos , Ciclofosfamida , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Dexametasona , Intervalo Livre de Doença , Etoposídeo , Feminino , Seguimentos , Humanos , Imunossupressores/administração & dosagem , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Agonistas Mieloablativos/administração & dosagem , Estudos Prospectivos , Transplante Autólogo , GencitabinaRESUMO
BACKGROUND: Chemotherapy adjuvant to surgery in metastatic melanoma has been evaluated in only a few prospective randomized trials. In the treatment of metastatic melanoma, dacarbazine has response rates of 15%-25% and in several studies, when combined with other alkylating agents, has yielded even higher response rates. Among the highest response rates are those achieved by using high-dose chemotherapy regimens combined with autologous bone marrow support (transplantation). PURPOSE: We conducted a prospective randomized clinical trial to test the efficacy of high-dose alkylating agents in combination with autologous bone marrow support given as adjuvant therapy for high-risk stage II (World Health Organization) melanoma. METHODS: Thirty-nine patients with metastases involving five or more lymph nodes were randomly assigned to one of two treatment arms within 8 weeks of lymphadenectomy: immediate treatment or observation only. The immediate-treatment arm consisted of 19 patients who, immediately after random assignment, received high-dose chemotherapy with alkylating agents, followed 3 days later by reinfusion of autologous bone marrow. The observation arm consisted of 20 patients who were observed until relapse (confirmed by biopsy) and were then treated with the identical high-dose alkylating agent chemotherapy followed by reinfusion of autologous bone marrow. Bone marrow was harvested from the patients under general anesthesia 1-2 weeks prior to chemotherapy and was cryopreserved. Chemotherapy consisted of intravenous administration of cyclophosphamide (1875 mg/m2 as a 1-hour infusion daily for 3 days), cisplatin (55 mg/m2 per day by continuous infusion over the same 72-hour period), and carmustine (BCNU) (600 mg/m2) given immediately after cisplatin on the 4th day as a 2-hour infusion. The total doses of the three drugs were 5625, 165, and 600 mg/m2, respectively. All patients received medical evaluations every 6-12 weeks over the study period. Kaplan-Meier estimates were used to determine the time to disease progression on the basis of intent to treat. RESULTS: There was no statistically significant difference in overall survival or in time to disease progression between the two treatment arms. However, the median time to progression was 16 weeks in the observation arm and 35 weeks in the immediate-treatment arm. CONCLUSIONS: Immediate adjuvant high-dose chemotherapy with alkylating agents followed by autologous bone marrow support more than doubled the time to disease progression compared with observation alone, though the difference was not statistically significant. No differences in overall survival were noted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Medula Óssea , Melanoma/terapia , Adulto , Carmustina/administração & dosagem , Cisplatino/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Metástase Linfática , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sobrevida , Transplante Autólogo , Resultado do TratamentoRESUMO
PURPOSE: We studied the effectiveness of prophylactic oral ciprofloxacin and rifampin on fever prevention in patients undergoing autologous bone marrow transplantation (ABMT) for breast cancer. Furthermore, we evaluated the toxicity and efficacy of empiric once-daily vancomycin and tobramycin for febrile neutropenia. PATIENTS AND METHODS: Ninety-nine assessable women received prophylactic ciprofloxacin and rifampin after high-dose chemotherapy (HDC) for advanced or high-risk primary breast cancer supported with either bone marrow and peripheral-blood progenitor cells (PBPCs) or bone marrow purged with chemotherapy and monoclonal antibodies. Neutropenic fever was treated with empiric once-daily vancomycin and tobramycin. Patients were compared with historic controls treated with the identical HDC and bone marrow support regimen. RESULTS: In patients treated with bone marrow and PBPCs, the incidence of fever during neutropenia was reduced by ciprofloxacin and rifampin from 98% to 57%. Documented infections were reduced from 42% to 13% (P < .01) and bacteremia from 18% to 0% (P < .001). In purged bone marrow recipients, the overall infection rate decreased from 74% to 17% (P < .001), and bacteremia from 29% to 7%. (P = .02). No patient developed breakthrough bacteremia or sepsis syndrome while on study. Serum creatinine level greater than 1.8 g/dL was noted in 7% of controls and 10% of study patients. Increased ototoxicity was not encountered with the higher peak concentrations of vancomycin and tobramycin. CONCLUSION: The therapeutic strategy of ciprofloxacin and rifampin followed by once-daily vancomycin and tobramycin markedly reduced the incidence of infection and virtually eliminated bacteremia in both purged and nonpurged bone marrow recipients. Once-daily vancomycin and tobramycin was safe and effective and, because of the ease of use, facilitates outpatient management of ABMT patients.
Assuntos
Infecções Bacterianas/prevenção & controle , Neoplasias da Mama/terapia , Quimioterapia Combinada/uso terapêutico , Febre/prevenção & controle , Neutropenia/prevenção & controle , Administração Oral , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Infecções Bacterianas/etiologia , Purging da Medula Óssea , Transplante de Medula Óssea/efeitos adversos , Ciprofloxacina/uso terapêutico , Esquema de Medicação , Quimioterapia Combinada/administração & dosagem , Quimioterapia Combinada/efeitos adversos , Feminino , Febre/etiologia , Humanos , Injeções Intravenosas , Pessoa de Meia-Idade , Neutropenia/etiologia , Rifampina/uso terapêutico , Transplante de Células-Tronco , Tobramicina/uso terapêutico , Vancomicina/uso terapêuticoRESUMO
PURPOSE: We studied high-dose cyclophosphamide, cisplatin, and carmustine (CPA/cDDP/BCNU) with autologous bone marrow support (ABMS) as consolidation after standard-dose adjuvant chemotherapy treatment of primary breast cancer involving 10 or more axillary lymph nodes. PATIENTS AND METHODS: One hundred two women with stage IIA, IIB, IIIA, or IIIB breast cancer involving 10 or more lymph nodes at surgery were registered; 85 were eligible, treated, and assessable. Patients were treated with four cycles of standard-dose cyclophosphamide, doxorubicin, and fluorouracil (CAF), followed by high-dose CPA/cDDP/BCNU with ABMS. RESULTS: Actuarial event-free survival for the study patients at a median follow-up of 2.5 years is 72% (95% confidence interval, 56% to 82%). Comparison to three historical or concurrent Cancer and Leukemia Group B (CALGB) adjuvant chemotherapy trials selected for similar patients showed event-free survival at 2.5 years to be between 38% and 52%. Therapy-related mortality was 12%; pulmonary toxicity of variable severity occurred in 31% of patients. Quality-of-life evaluations indicate that patients are functioning well without major impairments. CONCLUSION: High-dose consolidation with CPA/cDDP/BCNU and ABMS after standard-dose CAF results in a decreased frequency of relapse in patients with high-risk primary breast cancer compared with historical series at the median follow-up of 2.5 years. Evaluation in a prospective, randomized trial is warranted and currently underway.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Neoplasias da Mama/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transplante de Medula Óssea/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Carmustina/administração & dosagem , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Pessoa de Meia-Idade , Taxa de Sobrevida , Transplante AutólogoRESUMO
PURPOSE: A prospective study to determine the feasibility of high-dose chemotherapy (HDC) and autologous stem-cell rescue (ASCR) in the outpatient setting. METHODS: One hundred thirteen consecutive patients underwent 165 cycles of HDC/ASCR for a variety of malignancies. HDC regimens were disease-specific. Initially, patients were hospitalized for HDC, discharged on completion, and maintained as outpatients unless toxicities required rehospitalization (subtotal outpatient transplantation [STOT]). Once this was established as safe, a total outpatient transplant (TOT) program was developed in which patients received all of the HDC, as well as supportive care, as outpatients. Patients who declined the outpatient programs received the same HDC and supportive care as inpatients. RESULTS: In 140 of 165 (85%) HDC cycles, patients agreed to participate in one of the outpatient transplant programs. Five patients in the STOT program could not be discharged from the hospital because of toxicities that developed during HDC; thus, 135 patients were monitored the outpatient setting, 95 (70%) of whom were never readmitted. The mean +/- SEM total hospital length of stay (LOS), including all readmissions and excess days after chemotherapy, was 18.33 +/- 5.06 days for patients who refused the outpatient program, 8.22 +/- 5.76 days for patients in the STOT program, and 2.81 +/- 7.66 days for those in the TOT program (P < .001). One treatment-related death occurred in each treatment setting: day 120 inpatient, day 17 STOT, and day 110 TOT. CONCLUSION: Outpatient management of HDC/ASCR is safe and acceptable for the vast majority of patients. The STOT program resulted in significant reduction in hospital LOS, while the TOT program appears equally safe and further reduces LOS. Hospitalization for HDC/ASCR is unnecessary in most patients.
Assuntos
Assistência Ambulatorial , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Neoplasias/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Estudos de Viabilidade , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Tempo de Internação , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Avaliação de Programas e Projetos de Saúde , Estudos ProspectivosRESUMO
PURPOSE: The sequence in which chemotherapeutic agents are administered can alter their pharmacokinetics, therapeutic effect, and toxicity. We evaluated the pharmacokinetics and pharmacodynamics of docetaxel and topotecan when coadministered on two different sequences of administration. PATIENTS AND METHODS: On cycle 1, docetaxel was administered as a 1-hour infusion at 60 mg/m(2) without filgrastim and at 60, 70, and 80 mg/m(2) with filgrastim on day 1, and topotecan was administered at 0.75 mg/m(2) as a 0.5-hour infusion on days 1 to 4. On cycle 2, topotecan was administered on days 1 to 4, and docetaxel was administered on day 4. Cycles were repeated every 21 days. Blood samples for high-performance liquid chromatography measurement of docetaxel (CL(DOC)) and topotecan (CL(TPT)) total clearance were obtained on day 1 of cycle 1 and day 4 of cycle 2. CL(DOC) and CL(TPT) were calculated using compartmental methods. RESULTS: Mean +/- SD CL(DOC) in cycles 1 and 2 were 75.9 +/- 79.6 L/h/m(2) and 29.2 +/- 17.3 L/h/m(2), respectively (P: <.046). Mean +/- SD CL(TPT) in cycles 1 and 2 were 8.5 +/- 4.4 L/h/m(2) and 9.3 +/- 3.4 L/h/m(2), respectively (P: >. 05). Mean +/- SD neutrophil nadir in cycles 1 and 2 were 4,857 +/- 6, 738/microL and 2,808 +/- 4,518/microL, respectively (P: =.02). CONCLUSION: Administration of topotecan on days 1 to 4 and docetaxel on day 4 resulted in an approximately 50% decrease in docetaxel clearance and was associated with increased neutropenia.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Paclitaxel/análogos & derivados , Taxoides , Adulto , Idoso , Docetaxel , Esquema de Medicação , Interações Medicamentosas , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Contagem de Leucócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Contagem de Plaquetas/efeitos dos fármacos , Proteínas Recombinantes , Topotecan/administração & dosagem , Topotecan/farmacocinéticaRESUMO
High-dose chemotherapy (HDC) with autologous stem cell support has led to improved response rates, and in some cases, improved survival in a variety of different malignancies. Since alkylating agents are the most active class of compounds in malignant melanoma, attempts have been made to dose-intensify therapy using autologous bone marrow for hematologic support. Numerous phase I/II studies of different alkylating agents, either alone or in combination, have been reported. These results are characterized by high overall response rates, compared to lower-dose therapy, but few complete responses and disappointingly short remission durations. Some studies indicate that tumors in the skin or lymph nodes are more responsive to this approach than visceral or bone metastases. A single trial of HDC in the high-risk, surgical adjuvant setting showed that time to progression was more than doubled, although the result was not statistically significant because of the low power of the trial. More encouraging results may come from the combination of the cytoreductive capacity of HDC combined with immune augmentation from IL-2, interferon or similar cytokines, especially when combined with peripheral blood progenitor cells which induce faster recovery of the immune system.
Assuntos
Antineoplásicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Melanoma/terapia , Terapia Combinada , Humanos , Transplante AutólogoRESUMO
We evaluated the efficacy, toxicity and feasibility of two cycles of high-dose chemotherapy (HDC), each supported with mobilized peripheral blood progenitor cells (PBPC). Ninety-six patients with metastatic or high-risk cancers received disease-specific HDC regimens. The first cycle consisted of cyclophosphamide 6000 mg/m2, thiotepa 500 mg/m2 and carboplatin 1200 mg/m2. Alternatively, some patients received etoposide 1800 mg/m2 substituted for thiotepa. A second cycle was planned 6-8 weeks later and consisted of mitoxantrone 60 mg/m2 with either melphalan 140 mg/m2 or thiotepa 600 mg/m2. PBPC were mobilized with either growth factor alone or cyclophosphamide followed by growth factor(s). Thirty-four of 96 enrolled patients (35%) did not receive the second cycle. The reasons were: patient refusal (15); insurance refusal (three); toxicities of cycle 1 (seven); no response to cycle 1 (four); and inadequate mobilization or poor engraftment, (five). Of the 33 patients who entered cycle 2 with measurable disease, 28 demonstrated further response after cycle 2 (including 10 who entered CR). One patient died of toxicity after each cycle. Hematologic recovery was rapid and complete in most patients. Tandem cycles of high-dose chemotherapy supported by PBPC are feasible and safe, although many patients fail to receive the second treatment. Preliminary evaluation shows evidence of further antitumor efficacy following cycle 2.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças da Medula Óssea/terapia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Transplante de Células-Tronco Hematopoéticas , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças da Medula Óssea/induzido quimicamente , Transplante de Medula Óssea , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Esquema de Medicação , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Estudos de Viabilidade , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucaférese , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Mitoxantrona/efeitos adversos , Neoplasias/mortalidade , Aceitação pelo Paciente de Cuidados de Saúde , Indução de Remissão , Terapia de Salvação , Tiotepa/administração & dosagem , Tiotepa/efeitos adversos , Condicionamento Pré-Transplante , Transplante Autólogo , Resultado do TratamentoRESUMO
High-dose cyclophosphamide (CY) is associated with a high risk of hemorrhagic cystitis. The reported frequency ranges from 6.5 to 52% despite the use of hydration protocols. The current study reports a hyperhydration and continuous bladder irrigation protocol which resulted in a very low incidence of microscopic hematuria and no reported cases of visible hematuria. Patients received baseline fluids at 200 ml/m2/h during chemotherapy. Additional fluid boluses were given if urine output fell below 200 ml/h. Bladder irrigation was performed at a rate of 1 l/h during and for 24 h after high-dose CY. Three hundred three evaluable patients with solid tumors received high-dose chemotherapy with CY at a dose of 5625 mg/m2 over 3 days. Patients also received cisplatin 165 mg/m2 and carmustine 600 mg/m2. Some patients received thiotepa 300-750 mg/m2 instead of carmustine. The overall incidence of microscopic hematuria (> 15 RBCs per high power field) was 19%, with only 11% of patients experiencing more than 50 RBCs per high power field. No patient developed visible hematuria or symptomatic hematuria requiring intervention. These results using aggressive hyperhydration and high volumes of continuous bladder irrigation are among the best reported following high-dose CY chemotherapy.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Ciclofosfamida/efeitos adversos , Cistite/prevenção & controle , Hematúria/prevenção & controle , Humanos , Transplante AutólogoRESUMO
We report on three patients with multiple myeloma who developed drug-induced pneumonitis 1-2(1/2) months following maintenance (post autologous transplantation) chemotherapy with CDEP (cyclophosphamide, dexamethasone, etoposide, cisplatin) and 6-20 months after exposure to carmustine (BCNU) 300 mg/m(2), used in combination with melphalan 140 mg/m(2), as pre-transplant conditioning regimen. All patients had either a proven (two) or suspected (one) fungal pneumonia and were treated with liposomal amphotericin B. Dyspnea, fever and cough were the prominent clinical symptoms, while air-space disease with ground glass appearance was seen radiographically. Histologic features typical for drug-induced lung injury were detected. All patients had a dramatic, clinical and radiographic response to a brief course of corticosteroids. Although CDEP-induced pneumonitis appears to be a rare complication, its early recognition and prompt treatment, as well as its possible association with preceding fungal infection may have important clinical implications.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pneumopatias Fúngicas/induzido quimicamente , Idoso , Carmustina/administração & dosagem , Carmustina/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Terapia Combinada/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Pneumopatias Fúngicas/patologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/terapia , Pneumonia por Pneumocystis/induzido quimicamente , Pneumonia por Pneumocystis/patologia , Síndrome , Condicionamento Pré-Transplante/efeitos adversosRESUMO
High-dose chemotherapy and stem cell rescue is increasingly being delivered in the outpatient setting. Such intensive outpatient management programs have reduced the total hospital length of stay without compromising clinical outcomes. However, a detailed financial analysis of outpatient programs has not been performed. These data are the results of a prospective study of 94 patients receiving high-dose chemotherapy and autologous peripheral blood stem cell transplant in one of three settings: traditional inpatient, partial outpatient, total outpatient. Patients were allowed to choose their own treatment setting based upon the availability of a caregiver and personal preference. Total hospital length of stay and the actual cost and charges for each patient were monitored prospectively. The patients in the three groups were well balanced with regard to age and functional status prior to high-dose chemotherapy. The average length of stay was reduced from 17.3 to 8.2 to 2.7 days in the three different treatment settings (P < 0.01). Mean procedure costs were reduced from $39.7 thousand (US dollars) to $36.2 thousand to $29.4 thousand in the three treatment settings (P < 0.029). No differences in toxicity or overall response to therapy was noted. High-dose chemotherapy and stem cell rescue can be safely administered in the outpatient setting and results in significant cost savings.
Assuntos
Assistência Ambulatorial/economia , Transplante de Células-Tronco Hematopoéticas/economia , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto , Idoso , Antineoplásicos/economia , Antineoplásicos/uso terapêutico , Terapia Combinada , Custos e Análise de Custo , Honorários e Preços , Preços Hospitalares , Custos Hospitalares , Humanos , Tempo de Internação , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Estudos Prospectivos , Segurança , Transplante Autólogo , Resultado do TratamentoRESUMO
The administration of recombinant human interleukin-1 beta (rhIL-1 beta) stimulates pluripotent cell growth and reduces mortality from infection in animal models. In this phase I trial, rhIL-1 beta (0.02-0.50 microgram/kg) was administered by 30-minute intravenous infusion once daily for 2 or 5 consecutive days. The dose was escalated with the subsequent cycle in the same patient if no hematologic response was observed. Nineteen patients with severe bone marrow failure received 60 courses of IL-1 beta. Diagnoses included autologous bone marrow transplant (BMT) (n = 5), allogeneic BMT (n = 7) or idiopathic aplastic anemia (n = 6) and 1 patient with chronic myeloid leukemia. Toxicities included fever (89%), chills (85%), hypertension (89%), hypotension (57%) and headache (95%). No complications were life-threatening and all either spontaneously resolved or were managed pharmacologically. In 8 of 19 patients there was an acute, transient increase in neutrophil counts. In 2 patients there was a transient increase in platelet count; however, no durable, clinically significant effects on peripheral blood counts were observed. In conclusion, administration of rhIL-1 beta in this population of patients had limited efficacy and moderate toxicity.
Assuntos
Doenças da Medula Óssea/terapia , Interleucina-1/uso terapêutico , Adolescente , Adulto , Anticorpos/análise , Doenças da Medula Óssea/sangue , Criança , Pré-Escolar , Feminino , Humanos , Interleucina-1/administração & dosagem , Interleucina-1/efeitos adversos , Contagem de Leucócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Proteínas Recombinantes/uso terapêuticoRESUMO
The purpose of the study was to examine the yield of CD34(+) cells, response rates, and toxicity of high-dose cyclophosphamide with or without etoposide in patients with multiple myeloma. In total, 77 myeloma patients received either cyclophosphamide 4.5 g/m(2) (n=28) alone or with etoposide 2 g/m(2) (n=49) in a nonrandomized manner, followed by G-CSF 10 microg/kg/day for the purpose of stem cell mobilization. The effects of various factors on CD34(+) cell yield, response rate and engraftment were explored. A median of 22.39 x 10(6) CD34(+) cells/kg were collected on the first day of leukapheresis (range 0.59-114.71 x 10(6)/kg) in 71 (92%) of patients. Greater marrow plasma cell infiltration (P=0.02) or prior radiation therapy (P=0.02) adversely affected CD34(+) cell yield. In total, 45% of patients receiving cyclophosphamide and 56% of those receiving cyclophosphamide/etoposide had at least a minimum response by EBMT criteria. In all, 25% of patients who received cyclophosphamide alone vs 75.5% of patients who received combined chemotherapy required hospitalization mainly for treatment of neutropenic fever. Cyclophosphamide alone is associated with impressive CD34(+) cell yields and clear antimyeloma activity. The addition of etoposide resulted in increased toxicity without significant improvement in CD34(+) cell yield or response rates.
Assuntos
Ciclofosfamida/administração & dosagem , Etoposídeo/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Adulto , Idoso , Antígenos CD34/análise , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Ciclofosfamida/toxicidade , Etoposídeo/toxicidade , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/normas , Humanos , Leucaférese/métodos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Resultado do TratamentoRESUMO
The purpose of the study was to assess the toxicity and efficacy of an oral, combination antiemetic regimen including granisetron (Kytril; SmithKline Beecham Pharmaceuticals, Philadelphia, PA, USA) in the setting of highly emetogenic conditioning chemotherapy for stem cell transplantation. Antiemetic prophylaxis consisted of oral granisetron 2 mg once daily, oral prochlorperazine 10 mg q 6 h and oral dexamethasone 4 mg q 6 h, beginning 1 h prior to chemotherapy on each of the 4 days of chemotherapy and continuing until 24 h after the completion of high-dose chemotherapy (HDC). Patients received either CVP (cyclophosphamide 6 g/m2, VP-16 1800 mg/m2 and carboplatin 1200 mg/m2) or CTP (thiotepa 500 mg/m2 in place of VP-16) in four daily doses given over 4 h from days -4 to -1. Previously mobilized and cryopreserved peripheral blood stem cells (PBSC) were reinfused on day +1. Evaluation of nausea, emetic episodes (EE), adverse events, and rescue medications were recorded on a daily patient diary. Thirty-six patients were entered. Fifty-three percent (95% CI = 37-75%) of patients achieved complete response for emesis (CR = 0 EE/24 h) and 75% (95% CI = 58-90%) had combined complete and major response (CR+MR = 0-3 EE/24 h) during all 5 of the treatment days. During the 5 study days, the average number of patient-days with no emesis was 3.7 (74%) and with 1-3 EE was 4.3 (86%). On days -4, -3, -2, -1 and 0, the combined CR+MR rate for emesis was 97, 92, 86, 78 and 75%, respectively. Nausea was absent or mild on all 5 study days in 57% (95% CI = 37-75%). Eight patients had severe late-onset emesis occurring on days +1 to +3 after reinfusion of stem cells. No clinically significant toxicities attributable to the antiemetic regimen were observed. An all oral antiemetic regimen of granisetron, prochlorperazine and dexamethasone appears to be safe and highly effective in patients receiving multiple, daily, high-dose chemotherapy regimens. This regimen offers the advantage of cost-savings, a low side-effect profile and ease of administration in the predominately outpatient setting of HDC with peripheral blood stem cell transplant (PBSCT).
Assuntos
Antieméticos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transplante de Células-Tronco Hematopoéticas , Administração Oral , Adulto , Antieméticos/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Tolerância a Medicamentos , Feminino , Granisetron/administração & dosagem , Granisetron/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Proclorperazina/administração & dosagem , Proclorperazina/efeitos adversos , Fatores de TempoRESUMO
Four patients with chronic myelogenous leukemia (CML) that was refractory to interferon alpha (two patients) or imatinib mesylate (two patients), and who lacked donors for allogeneic stem cell transplantation, received autotransplants followed by infusions of ex vivo costimulated autologous T cells. At day +30 (about 14 days after T-cell infusion), the mean CD4+ cell count was 481 cells/microl (range 270-834) and the mean CD8+ count was 516 cells/microl (range 173-1261). One patient had a relative lymphocytosis at 3.5 months after T-cell infusion, with CD4 and CD8 levels of 750 and 1985 cells/microl, respectively. All the four patients had complete cytogenetic remissions early after transplantation, three of whom also became PCR negative for the bcr/abl fusion mRNA. One patient, who had experienced progressive CML while on interferon alpha therapy, became PCR- post transplant, and remained in a molecular CR at 3.0 years of follow-up. All the four patients survived at 6, 9, 40, and 44 months post transplant; the patient who remained PCR+ had a cytogenetic and hematologic relapse of CML, but entered a molecular remission on imatinib. Autotransplantation followed by costimulated autologous T cells is feasible for patients with chronic phase CML, who lack allogeneic donors and can be associated with molecular remissions.
Assuntos
Transferência Adotiva/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , RNA Neoplásico/análise , Transferência Adotiva/efeitos adversos , Adulto , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Seguimentos , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Ativação Linfocitária , Contagem de Linfócitos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Indução de Remissão/métodos , Terapia de Salvação/métodos , Linfócitos T/imunologia , Linfócitos T/transplante , Fatores de Tempo , Transplante AutólogoRESUMO
We studied the effects of escalating doses of recombinant human IL-1 beta in patients receiving high-dose chemotherapy and ABMT for metastatic breast cancer or malignant melanoma. Sixteen patients received IL-1 beta, 4 to 32 ng/kg/day administered subcutaneously for 7 days beginning 3 h after bone marrow infusion. Three patients at the highest dose level also received G-CSF following completion of IL-1 beta. All patients completed the 7 days of therapy. The majority of patients experienced chills and fever following one or more injections, and seven had severe pain at the injection site. There was one episode of hypotension and one episode of transient confusion at the highest dose level; other significant toxicity was not identified. Recovery of neutrophils to > 0.5 x 10(9)l and platelet transfusion independence occurred at a median of 23 and 22 days, respectively, which was comparable to historical controls. The mean number of bone marrow colony-forming unit granulocyte-macrophage (CFU-GM) per 10(5) mononuclear cells on day +21 post-ABMT was more than twice that of control patients or patients receiving G-CSF or GM-CSF. A linear correlation was found between the dose of IL-1 beta and endogenous concentrations of several cytokines. These patients also displayed significantly higher concentrations of endogenous G-CSF compared to historical controls receiving GM-CSF. While IL-1 beta was moderately toxic and had no effect on recovery of peripheral blood counts after ABMT, the increased number of bone marrow CFU-GM suggests that the addition of G- or GM-CSF to a short course of IL-1 beta may accelerate hematologic recovery.
Assuntos
Antineoplásicos/administração & dosagem , Transplante de Medula Óssea , Neoplasias da Mama/terapia , Interleucina-1/administração & dosagem , Melanoma/terapia , Neoplasias Cutâneas/terapia , Adulto , Antineoplásicos/efeitos adversos , Neoplasias da Mama/patologia , Ensaio de Unidades Formadoras de Colônias , Terapia Combinada , Feminino , Fator Estimulador de Colônias de Granulócitos/biossíntese , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Interleucina-1/efeitos adversos , Interleucina-1beta , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Neoplasias Cutâneas/patologia , Transplante AutólogoRESUMO
We evaluated 120 leukapheresis procedures (93 patients), in order to detect clinical factors that influence the efficiency of CD34+ collection using Cobe Spectra trade mark cell separators. Hematocrit was >27% and platelet count >30 000/microl in >95% of patients. Platelet transfusions were given if the postprocedure count was &<20 000/microl. Multiple regression analysis was used to analyze putative factors, and a predictive equation defined by stepwise regression modeling. The mean efficiency was 0.59 (s.d. 0.27). Sex (M>F; P=0.01), the volume processed (inversely; P=0.01) and CD34+ cell count (inversely; P=0.04) were associated with efficiency, whereas hematocrit, platelet or leukocyte count, catheter type and patient weight were not. The effect size for predictive factors was small (R(2)=0.21). Adverse events were limited to hypocalcemia. We conclude that female sex, volume processed and CD34+ cell count adversely influence the efficiency of CD34+ cell leukapheresis. However, the impact of volume and CD34+ cell count is small, and likely to be offset by the influence of these same factors on overall yield. Leukapheresis appears to be safe and efficient for autologous blood and marrow transplantation patients with hematocrit >27% and platelet count >30 000/microl.
Assuntos
Antígenos CD34/sangue , Células-Tronco Hematopoéticas/citologia , Leucaférese/métodos , Transplante de Células-Tronco/métodos , Antígenos CD4/sangue , Ciclofosfamida/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Hematócrito , Mobilização de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Contagem de Plaquetas , Proteínas Recombinantes , Reprodutibilidade dos Testes , Transplante de Células-Tronco/efeitos adversos , Resultado do TratamentoRESUMO
Relapse remains a major cause of treatment failure after autotransplantation (auto-PBSCT) for Hodgkin's disease (HD). The administration of non-crossresistant therapies during the post-transplant period may delay or prevent relapse. We prospectively studied the role of consolidation chemotherapy (CC) after auto-PBSCT in 37 patients with relapsed or refractory HD. Patients received high-dose gemcitabine-BCNU-melphalan and auto-PBSCT followed by involved-field radiation and up to four cycles of the DCEP-G regimen, which consisted of dexamethasone, cyclophosphamide, etoposide, cisplatin, gemcitabine given at 3 and 9 months post transplant alternating with a second regimen (DPP) of dexamethasone, cisplatin, paclitaxel at 6 and 12 months post transplant. The probabilities of event-free survival (EFS) and overall survival (OS) at 2.5 years were 59% (95% CI=42-76%) and 86% (95% CI=71-99%), respectively. In all, 17 patients received 54 courses of CC and 15 were surviving event free (2.5 years, EFS=87%). There were no treatment-related deaths during or after the CC phase. Post-transplant CC is feasible and well tolerated. The impact of this approach on EFS should be evaluated in a larger, randomized study.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Doença de Hodgkin/terapia , Terapia de Salvação/métodos , Adolescente , Adulto , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Dexametasona/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Doença de Hodgkin/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Salvação/mortalidade , Prevenção Secundária , Análise de Sobrevida , Transplante Autólogo , GencitabinaRESUMO
High-dose chemotherapy using melphalan (HDMEL) is an important component of many conditioning regimens that are given before autologous hematopoietic stem cell transplantation (AHSCT). In contrast to the situation in myeloma, and to a lesser degree acute leukemia, only a very limited published experience exists with the use of HDMEL conditioning as a single agent in doses requiring AHSCT for lymphoma, both Hodgkin lymphoma (HL) and especially non-Hodgkin lymphoma (NHL). Thus, we report results of treating 26 lymphoma patients (22 with NHL and four with HL) with HDMEL 220-300 mg/m(2) plus amifostine (AF) cytoprotection and AHSCT as part of a phase I-II trial. Median age was 51 years (range 24-62 years); NHL histology was varied, but was aggressive (including transformed from indolent) in 19 patients, indolent in two patients and mantle cell in one. All 26 patients had been extensively treated; 11 were refractory to the immediate prior therapy on protocol entry and two had undergone prior AHSCT. All were deemed ineligible for other, 'first-line' AHSCT regimens. Of these 26 patients, 22 survived to initial tumor evaluation on D +100. At this time, 13 were in complete remission, including four patients who were in second CR before HDMEL+AF+AHSCT. Responses occurred at all HDMEL doses. Currently, seven patients are alive, including five without progression, with a median follow-up in these latter patients of D +1163 (range D +824 to D +1630); one of these patients had a nonmyeloablative allograft as consolidation on D +106. Conversely, 14 patients relapsed or progressed, including five who had previously achieved CR with the AHSCT procedure. Two patients, both with HL, remain alive after progression; one is in CR following salvage radiotherapy. Six patients died due to nonrelapse causes, including two NHL patients who died while in CR. We conclude that HDMEL+AF+AHSCT has significant single-agent activity in relapsed or refractory NHL and HL. This experience may be used as a starting point for subsequent dose escalation of HDMEL (probably with AF) in established combination regimens.
Assuntos
Amifostina/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/terapia , Linfoma não Hodgkin/terapia , Melfalan/administração & dosagem , Protetores contra Radiação/administração & dosagem , Adulto , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Condicionamento Pré-Transplante/métodos , Transplante AutólogoRESUMO
Disease relapse occurs in 50% or more of patients who are autografted for relapsed or refractory lymphoma (NHL) or Hodgkin's disease (HD). The administration of non-cross-resistant therapies during the post-transplant phase could possibly control residual disease and delay or prevent its progression. To test this approach, 55 patients with relapsed/refractory or high-risk NHL or relapsed/refractory HD were enrolled in the following protocol: stem cell mobilization: cyclophosphamide (4.5 g/m(2)) + etoposide (2.0 g/m(2)) followed by GM-CSF or G-CSF; high-dose therapy: gemcitabine (1.0 g/m(2)) on day -5, BCNU (300 mg/m(2)) + gemcitabine (1.0 g/m(2)) on day -2, melphalan (140 mg/m(2)) on day -1, blood stem cell infusion on day 0; post-transplant immunotherapy (B cell NHL): rituxan (375 mg/m(2)) weekly for 4 weeks + GM-CSF (250 microg thrice weekly) (weeks 4-8); post-transplant involved-field radiotherapy (HD): 30-40 Gy to pre-transplant areas of disease (weeks 4-8); post-transplant consolidation chemotherapy (all patients): dexamethasone (40 mg daily)/cyclophosphamide (300 mg/m(2)/day)/etoposide (30 mg/m(2)/day)/cisplatin (15 mg/m(2)/day) by continuous intravenous infusion for 4 days + gemcitabine (1.0 g/m(2), day 3) (months 3 + 9) alternating with dexamethasone/paclitaxel (135 mg/m(2))/cisplatin (75 mg/m(2)) (months 6 + 12). Of the 33 patients with B cell lymphoma, 14 had primary refractory disease (42%), 12 had relapsed disease (36%) and seven had high-risk disease in first CR (21%). For the entire group, the 2-year Kaplan-Meier event-free survival (EFS) and overall survival (OS) were 30% and 35%, respectively, while six of 33 patients (18%) died before day 100 from transplant-related complications. The rituxan/GM-CSF phase was well-tolerated by the 26 patients who were treated and led to radiographic responses in seven patients; an eighth patient with a blastic variant of mantle-cell lymphoma had clearance of marrow involvement after rituxan/GM-CSF. Of the 22 patients with relapsed/refractory HD (21 patients) or high-risk T cell lymphoblastic lymphoma (one patient), the 2-year Kaplan-Meier EFS and OS were 70% and 85%, respectively, while two of 22 patients (9%) died before day 100 from transplant-related complications. Eight patients received involved field radiation and seven had radiographic responses within the treatment fields. A total of 72 courses of post-transplant consolidation chemotherapy were administered to 26 of the 55 total patients. Transient grade 3-4 myelosuppression was common and one patient died from neutropenic sepsis, but no patients required an infusion of backup stem cells. After adjustment for known prognostic factors, the EFS for the cohort of HD patients was significantly better than the EFS for an historical cohort of HD patients autografted after BEAC (BCNU/etoposide/cytarabine/cyclophosphamide) without consolidation chemotherapy (P = 0.015). In conclusion, post-transplant consolidation therapy is feasible and well-tolerated for patients autografted for aggressive NHL and HD and may be associated with improved progression-free survival particularly for patients with HD.