RESUMO
Treating metastatic malignancies to the central nervous system (CNS) is challenging because many drugs cannot cross the blood-brain-barrier (BBB). Direct intrathecal (IT) drug administration into the cerebrospinal fluid (CSF) is a strategy to overcome this problem. Thiotepa has effective CNS penetration but its popularity has waned over the last two decades due to concerns about its efficacy and potential systemic toxicity. This review evaluates the available evidence for the use of IT thiotepa in hematologic malignancies and non-CNS solid tumors with leptomeningeal disease metastases (LMD). Our search shows that IT thiotepa is a reasonable alternative in hematologic malignancies and LMD due to solid organ malignancies. This suggests a potential role of IT thiotepa in second-or third-line treatment or a substitute role in cases of drug-shortages and adverse effects with other agents. Future research should focus on rigorous comparative trials to establish its definitive role in the evolving landscape of CNS-directed chemotherapy.
Assuntos
Neoplasias do Sistema Nervoso Central , Injeções Espinhais , Tiotepa , Humanos , Tiotepa/administração & dosagem , Tiotepa/efeitos adversos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/secundário , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/secundárioRESUMO
Busulfan and cyclophosphamide (BuCy)-based regimen has been used as a standard myeloablative chemotherapy for haematopoietic stem cell transplantation in thalassemia. However, treosulfan-based conditioning regimen has emerged due to concerns of toxicities. We retrospectively analysed the safety and efficacy of fludrabine/Bu/Cy/antithymocyte globulin (ATG) versus treosulfan/thiotepa/fludrabine regimens for Hematopoietic Stem Cell Transplant (HSCT) in transfusion-dependent thalassemia (TDT) conducted at our institute (2013-2021). In 75 patients, 36 (48%) received Flu/Bu/Cy/ATG whereas 39 (52%) received Treo/Thio/Flu. Median age was 6 (1-12) and 9 (1-15) years, respectively. Number of patients with Classes I, II, and III were 14, 10, and 12 in Flu/Bu/Cy/ATG versus 2, 19, and 18 in Treo/Thio/Flu group, respectively. Graft was growth factor mobilized bone marrow in Flu/Bu/Cy/ATG versus peripheral blood stem cell in Treo/Thio/Flu group. Mean stem cell dose was 3.82 (2.2-9.1) versus 5 (1.65-8.01) 106 /kg in Flu/Bu/Cy/ATG versus Treo/Thio/Flu group, respectively. Neutrophils and platelets engrafted at a median of 16 (14-21) and 16 (9-47) days in Flu/Bu/Cy/ATG and 15 (10-20) and 13 (9-41) days in Treo/Thio/Flu group. Median duration of follow-up was 28 (23-32.9) months. Five (6.6%) patients had rejection (all secondary). Venoocclusive disease was observed in 2 (5.7%) versus 4 (10.3%) patients (p = .047), respectively. Flu/Bu/Cy/ATG had 4 (11.4%) patients with acute GVHD versus 15 (38.5%) patients which had significant impact on survival (p = .038). We observed chronic GVHD in 4 (11.4%) and 11 (28.2%) patients, respectively, with significant impact on survival (p = .031). Four (5.1%) patients had TRM in Treo/Thio/Flu group, in contrast to none in Flu/Bu/Cy/ATG group. Mixed chimerism was common in Flu/Bu/Cy/ATG {20 (57.1%)} versus Treo/Thio/Flu group {12 (30.1%)}. Five-year Event Free Survival (EFS) and OS of entire cohort were 87% + 4% and 94% + 3%, respectively. Estimated TFS, EFS, OS of Flu/Bu/Cy/ATG versus Treo/Thio/Flu was 97.1% + 2.9% versus 89.2% + 5.1% (p = .251), 97 + 3% versus 80.7 + 6% (p = .041) and 100% versus 90.4 + 5% (p = .067), respectively. In our experience, Flu/Bu/Cy/ATG regimen is safe and effective even in high-risk TDT. However, one needs to be vigilant for mixed chimerism.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Talassemia , Adolescente , Soro Antilinfocitário/efeitos adversos , Bussulfano/efeitos adversos , Bussulfano/análogos & derivados , Criança , Pré-Escolar , Ciclofosfamida/efeitos adversos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intercelular , Estudos Retrospectivos , Talassemia/diagnóstico , Talassemia/terapia , Tiotepa/efeitos adversos , Condicionamento Pré-Transplante , Transplante Homólogo , Vidarabina/uso terapêuticoRESUMO
219 HIV-negative adults ≤70 years with primary CNS lymphoma (PCNSL) were enrolled in the randomized IELSG32 trial. Enrolled patients were randomly assigned to receive methotrexate-cytarabine (arm A), or methotrexate-cytarabine-rituximab (B), or methotrexate-cytarabine-thiotepa-rituximab (MATRix; arm C). A second randomization allocated patients with responsive/stable disease to whole-brain irradiation (WBRT) or carmustine-thiotepa-conditioned autologous transplantation (ASCT). First results, after a median follow-up of 30 months, showed that MATRix significantly improves outcome, with both WBRT and ASCT being similarly effective. However, sound assessment of overall survival (OS), efficacy of salvage therapy, late complications, secondary tumors, and cognitive impairment requires longer follow-up. Herein, we report the results of this trial at a median follow-up of 88 months. As main findings, MATRix was associated with excellent long-lasting outcome, with a 7-year OS of 21%, 37%, and 56% respectively for arms A, B, and C. Notably, patients treated with MATRix and consolidation had a 7-year OS of 70%. The superiority of arm B on arm A suggests a benefit from the addition of rituximab. Comparable efficacy of WBRT and ASCT was confirmed. Salvage therapy was ineffective; benefit was recorded only in patients with late relapse re-treated with methotrexate. Eight (4%) patients developed a second cancer. Importantly, MATRix and ASCT did not result in higher non-relapse mortality or second tumors incidence. Patients who received WBRT experienced impairment in attentiveness and executive functions, whereas patients undergoing ASCT experienced improvement in these functions as well as in memory and quality of life.
Assuntos
Neoplasias do Sistema Nervoso Central , Transplante de Células-Tronco Hematopoéticas , Linfoma , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Nervoso Central/patologia , Terapia Combinada , Citarabina , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Linfoma/etiologia , Linfoma/terapia , Metotrexato , Qualidade de Vida , Rituximab , Tiotepa/efeitos adversos , Transplante Autólogo/efeitos adversosRESUMO
Effective reinduction regimens are needed for children with relapsed and refractory acute myeloid leukemia (AML), as outcomes remain poor. Therapeutic options are limited in this heavily pretreated patient population, many of whom have reached lifetime recommended doses of anthracycline chemotherapy. The development of effective non-anthracycline-based salvage regimens is crucial to these patients who are at significant risk of life-threatening cardiotoxicity. We previously reported results of a phase 2 trial of a clofarabine-based regimen with topotecan, vinorelbine, and thiotepa (TVTC) in patients with relapsed acute leukemias. Here we report on an expanded bicenter cohort of 33 patients, <25 years of age, with relapsed/refractory AML treated with up to 2 cycles of the TVTC reinduction regimen from 2007 to 2018. The overall response rate, defined as complete remission or complete remission with partial recovery of platelet count, was 71.4% (95% confidence interval [CI], 41.9-91.6) for those patients in first relapse (n = 14) and 47.4% (95% CI, 24.4-71.1) for patients in second or greater relapse or with refractory disease. Responses were seen across multiple high-risk cytogenetic and molecular subtypes, with 84% of responders successfully bridged to allogeneic stem cell transplantation. The 5-year overall survival for patients in first relapse was 46.2% (95% CI, 19.1-73.3) and 50.0% (95% CI, 26.9-73.1) for patients who responded to TVTC. For pediatric and young adult patients with relapsed/refractory AML, TVTC reinduction compares favorably with currently used salvage regimens and warrants further exploration.
Assuntos
Leucemia Mieloide Aguda , Tiotepa , Antraciclinas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Clofarabina/uso terapêutico , Humanos , Leucemia Mieloide Aguda/etiologia , Recidiva , Tiotepa/efeitos adversos , Topotecan/efeitos adversos , Vinorelbina/uso terapêutico , Adulto JovemRESUMO
Optimal conditioning for adults with acute lymphoblastic leukemia (ALL) treated with haploidentical hematopoietic cell transplantation (haplo-HCT) and post-transplant cyclophosphamide has not been established so far. We retrospectively compared outcomes for two myeloablative regimens: fludarabine + total body irradiation (Flu-TBI, n = 117) and thiotepa + iv. busulfan + fludarabine (TBF, n = 119). Patients transplanted either in complete remission (CR) or with active disease were included in the analysis. The characteristics of both groups were comparable except for patients treated with TBF were older. In univariate analysis the incidence of non-relapse mortality (NRM) at 2 years was increased for TBF compared to Flu-TBI (31% vs. 19.5%, p = 0.03). There was a tendency towards reduced incidence of relapse after TBF (p = 0.11). Results of multivariate analysis confirmed a reduced risk of NRM using Flu-TBI (HR = 0.49, p = 0.03). In the analysis restricted to patients treated in CR1 or CR2, the use of Flu-TBI was associated with a decreased risk of NRM (HR = 0.34, p = 0.009) but an increased risk of relapse (HR = 2.59, p = 0.01) without significant effect on survival and graft-versus-host disease. We conclude that for haplo-HCT recipients with ALL, Flu-TBI may be preferable for individuals at high risk of NRM while TBF should be considered in cases at high risk of relapse.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Bussulfano/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Estudos Retrospectivos , Tiotepa/efeitos adversos , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Irradiação Corporal Total/efeitos adversosRESUMO
Thiotepa, an antineoplastic ethylenimine alkylating agent that can penetrate the central nervous system, was recently approved in Japan as high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (HSCT) for patients with malignant lymphoma. To further evaluate the safety and efficacy of thiotepa, a multicenter, open-label, non-comparative, expanded access program was undertaken in Japan, including a larger population of Asian patients with malignant lymphoma. Intravenous thiotepa (200 mg/m2/day) was administered over 2 h on days -4 and -3 before scheduled HSCT, plus intravenous busulfan (0.8 mg/kg) over 2 h every 6 h on days -8, -7, -6 and -5. In the safety analysis population (N = 51), 25 patients (49.0%) had primary central nervous system lymphomas. The most common treatment-emergent adverse event was febrile neutropenia (49/51 [96.1%]). No unexpected safety events were observed, and no event resulted in death or treatment modification. Forty-seven patients (92.2%) had engraftment (neutrophil count ≥ 500/mm3 for three consecutive days after bone-marrow suppression and HSCT). The survival rate at day 100 post-transplantation was 100%. These data confirm the safety of thiotepa prior to autologous HSCT for patients with malignant lymphoma.Trial registration: JapicCTI-173654.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma/terapia , Pulsoterapia/métodos , Tiotepa/administração & dosagem , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Neutropenia Febril/induzido quimicamente , Feminino , Humanos , Infusões Intravenosas , Linfoma/mortalidade , Masculino , Segurança , Taxa de Sobrevida , Tiotepa/efeitos adversos , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: We hypothesized that the addition of 4 doses of abatacept to our standard acute graft-versus-host disease (GVHD) prophylaxis would reduce the incidence of day +100 severe acute GVHD in children with transfusion-dependent beta-thalassemia major undergoing a myeloablative allogeneic hematopoietic stem cell transplant (HSCT), without impacting engraftment. METHODS: Twenty-four children with beta-thalassemia major received abatacept at a dose of 10 mg/kg intravenously on days -1, +5, +14, and +28 after HSCT in addition to calcineurin inhibitors and methylprednisolone. Outcomes were compared to 8 beta-thalassemia patients who received standard acute GVHD prophylaxis. RESULTS: There was no difference in engraftment between the 2 groups. No patient had grades III-IV acute GVHD by day +100 in the abatacept cohort compared with 50% in the standard acute GVHD prophylaxis group (P = 0.001). Viral reactivation occurred in 5 children in the standard acute GVHD cohort and in 20 children in the abatacept cohort (P = 0.2). Thalassemia-free survival after HSCT was 100% in the abatacept cohort compared to 62.5% in the standard cohort at last follow-up (P = 0.007). CONCLUSIONS: Adding abatacept to our routine GVHD prophylaxis reduced the incidence of day +100 severe acute GVHD without impacting engraftment or survival.
Assuntos
Abatacepte/administração & dosagem , Bussulfano/administração & dosagem , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/administração & dosagem , Tiotepa/administração & dosagem , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Talassemia beta/cirurgia , Abatacepte/efeitos adversos , Adolescente , Bussulfano/efeitos adversos , Inibidores de Calcineurina/administração & dosagem , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Lactente , Masculino , Metilprednisolona/administração & dosagem , Estudos Retrospectivos , Tiotepa/efeitos adversos , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Talassemia beta/diagnósticoRESUMO
Autologous stem cell transplantation (ASCT) with high-dose thiotepa and busulfan is a treatment option for patients with central nervous system (CNS) lymphoma. We report here the occurrence of secondary failure of platelet recovery (SFPR) in three out of 24 patients who received high-dose thiotepa and busulfan followed by ASCT. Although there was no obvious abnormality in the primary platelet engraftment as well as the recovery of other blood cells, they developed SFPR with a median time to onset of day 38, and the platelets gradually recovered over several months with steroid therapy. During the same period, there was no development of SFPR among 50 patients who received ASCT with a conditioning regimen of MEAM (ranimustine, etoposide, cytarabine, and melphalan) or high-dose melphalan. However, one of the two patients who received a conditioning regimen of busulfan and melphalan developed SFPR, suggesting that the use of a busulfan-based conditioning regimen may be one of the risk factors for SFPR. It is important to be aware of this possible adverse effect of ASCT with high-dose thiotepa and busulfan to ensure timely diagnosis and prevention of subsequent serious complications.
Assuntos
Bussulfano/efeitos adversos , Neoplasias do Sistema Nervoso Central/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfoma/terapia , Tiotepa/efeitos adversos , Trombocitopenia/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Adulto , Idoso , Bussulfano/administração & dosagem , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Tiotepa/administração & dosagem , Fatores de Tempo , Condicionamento Pré-Transplante/métodos , Transplante AutólogoRESUMO
BACKGROUND: Treatment for malignant embryonal brain tumors in young children usually employs cycles of standardly dosed cisplatinum followed by high-dose carboplatinum-containing conditioning with single or tandem autologous stem cell rescue (HDC-ASCR). High-dose carboplatin is potentially nephrotoxic, and additive platinum exposure may acutely impact renal function. Aiming to determine if decrease in renal function during conditioning assessed prior to each carboplatin dose was associated with acute increases in creatinine, requirement for dialysis or transplant-related mortality (TRM). This was a retrospective study of consecutive patients with medulloblastoma (n = 15) / atypical teratoid/rhabdoid tumor (AT/RT, n = 5) receiving HDC-ASCR. Fifteen patients underwent 1 HDC-ASCR (carboplatin × 3 doses/ etoposide/ thiotepa) and 5 patients underwent at least 1 of 3 planned tandem HDC-ASCR (carboplatin × 2 doses/ thiotepa). Renal function was assessed by daily creatinine and nuclear medicine glomerular filtration rate (GFR)/ creatinine clearance before each carboplatin dose. RESULTS: In this cohort of 20 patients, 3 had doses of carboplatin omitted due to decreases in GFR: 1 did not develop nephrotoxicity, 1 experienced nephrotoxicity without need for dialysis, and 1 required dialysis temporarily but recovered renal function. Two patients did not have GFR changes but developed post-ASCR renal failure requiring dialysis and TRM. CONCLUSION: Daily assessment of renal function by GFR, prior each dose of carboplatin during HDC-ASCR, will help in protecting the kidney in heavily treated population of oncology/HSCT patients. Although the study had a small number of patients which is a major limitation of the study, but it points to a serious transplant-related morbidity and mortality. So, larger scale studies are needed to clarify the best approach to carboplatin dosing to insure the optimal balance between efficacy and toxicity.
Assuntos
Injúria Renal Aguda/prevenção & controle , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/terapia , Carboplatina/efeitos adversos , Taxa de Filtração Glomerular/efeitos dos fármacos , Condicionamento Pré-Transplante/efeitos adversos , Injúria Renal Aguda/sangue , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/mortalidade , Carboplatina/administração & dosagem , Criança , Pré-Escolar , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Creatinina/sangue , Relação Dose-Resposta a Droga , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Masculino , Meduloblastoma/mortalidade , Meduloblastoma/terapia , Estudos Retrospectivos , Tumor Rabdoide/mortalidade , Tumor Rabdoide/terapia , Teratoma/mortalidade , Teratoma/terapia , Tiotepa/administração & dosagem , Tiotepa/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Autólogo/métodos , Resultado do TratamentoRESUMO
Thiotepa is a common alkylating agent known to precipitate cutaneous reactions consistent with toxic erythema of chemotherapy, including erythema and hyperpigmentation. Herein, we describe an atypical case of malignant intertrigo involving preferential erythema and desquamation not only of skin folds but also of occluded areas after thiotepa-based conditioning. The diagnosis was complicated by concurrent stomatitis and oral petechiae in the setting of autologous stem cell transplant 11 days prior for diffuse large B-cell lymphoma. Histopathological examination from two cutaneous sites demonstrated epidermal dysmaturation and eccrine gland necrosis consistent with thiotepa-induced desquamation and not Stevens-Johnson syndrome or graft-versus-host-disease. Malignant intertrigo can present with extensive cutaneous involvement, as evidenced by our patient who had 25% body surface area affected. Mucosal involvement is common with most chemotherapeutic regimens and its presence should not deter the astute clinician from consideration of a diagnosis of toxic erythema of chemotherapy. No further interventions were needed and the patient healed spontaneously.
Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Erros de Diagnóstico , Hiperpigmentação/induzido quimicamente , Intertrigo/diagnóstico , Síndrome de Stevens-Johnson/diagnóstico , Tiotepa/efeitos adversos , Idoso , Humanos , Hiperpigmentação/diagnóstico , Hiperpigmentação/patologia , Intertrigo/induzido quimicamente , Intertrigo/patologia , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Estomatite/induzido quimicamenteRESUMO
BACKGROUND: Allogeneic stem cell transplantation is a potentially curative therapy for patients with acute myeloid leukemia (AML) after achieving complete remission (CR). The aim of this study is to evaluate the optimal dose of thiotepa, administered as part of the thiotepa-busulfan-fludarabine (TBF) conditioning regimen for allogeneic stem cell transplantation in adults with AML in CR. PATIENTS AND METHODS: In a retrospective multicenter analysis, we identified 240 patients allotransplanted from matched related or unrelated donors or T replete haplo-identical donors. We compared the transplantation outcomes of patients who received 5 mg/kg thiotepa and 2 days of intravenous busulfan at 6.4 mg/kg (T1B2F) versus those who received 10 mg/kg thiotepa with 2 days of intravenous busulfan at 6.4 mg/kg (T2B2F). The median follow-up was 20 months. RESULTS: On univariate analysis, the incidence of acute graft versus host disease (GVHD) grade II to IV was significantly lower in the T1B2F group (19%) versus 32% in the T2B2F group (P = .029). This result was confirmed on multivariate analysis; acute GVHD was higher for patients receiving T2B2F (hazard ratio, 2.22; P = .024). No significant change in non-relapse mortality, progression-free survival, or overall survival was observed between the 2 groups. CONCLUSION: T2B2F is associated with a higher incidence of acute GVHD compared with T1B2F. These results suggest that a lower dose-intensity of thiotepa and busulfan in the TBF regimen may yield better results in patients with AML in CR.
Assuntos
Bussulfano/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Tiotepa/administração & dosagem , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Adulto , Idoso , Aloenxertos , Bussulfano/efeitos adversos , Intervalo Livre de Doença , Seguimentos , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Tiotepa/efeitos adversos , Vidarabina/administração & dosagem , Vidarabina/efeitos adversosRESUMO
The International Extranodal Lymphoma Study Group-32 (IELSG32) randomized patients with primary central nervous system lymphoma (PCNSL) for induction treatment with methotrexate-cytarabine, methotrexate-cytarabine-rituximab, or methotrexate-cytarabine-thiotepa-rituximab (MATRix) and reported significantly improved complete remission with the MATRix regimen. This study assessed cost-effectiveness among these three induction strategies for PCNSL. A Markov model was developed based on the IELSG32 trial over a 20 year time horizon from the Canadian health care system perspective. Costs for induction, consolidation, inpatient treatment administration, follow-up, adverse events, relapsed disease, and palliative care were included. Methotrexate-cytarabine-rituximab was subject to extended dominance by the other two strategies. The MATRix regimen compared to methotrexate-cytarabine produced 3.05 quality-adjusted life year (QALY) gains at added costs of $75,513, resulting in an incremental cost-effectiveness ratio of $24,758/QALY gained. The MATRix regimen was the optimal strategy in the majority of simulations (98% probability at willingness-to-pay of $50,000/QALY gained) and results appeared robust across sensitivity analyses.
Assuntos
Neoplasias do Sistema Nervoso Central , Citarabina , Metotrexato , Rituximab , Tiotepa , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Canadá , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Análise Custo-Benefício , Citarabina/uso terapêutico , Humanos , Metotrexato/uso terapêutico , Rituximab/efeitos adversos , Tiotepa/efeitos adversosRESUMO
The MATRix chemoimmunotherapy regimen is highly effective in patients with newly diagnosed primary diffuse large B-cell lymphoma of the central nervous system (PCNSL). However, nothing is known about its feasibility and efficacy in everyday practice, where patients are more often older/frailer than those enrolled in clinical trials. We conducted a retrospective study addressing tolerability/efficacy of MATRix in 156 consecutive patients with newly diagnosed PCNSL treated outside a clinical trial. Median age and ECOG Performance Status of considered patients were 62 years (range 28-78) and 2 (range 0-4). The overall response rate after MATRix was 79%. Nine (6%) treatment-related deaths were recorded. After a median follow-up of 27.4 months (95% confidence interval [CI] 24.4-31.9%), the two-year progression-free and overall survival were 56% (95% CI 48.4-64.9%) and 64.1% (95% CI 56.7-72.5%) respectively. Patients not eligible for the IELSG32 trial were treated with lower dose intensity and had substantially worse outcomes than those fulfilling inclusion criteria. This is the largest series of PCNSL patients treated with MATRix outside a trial and recapitulates the IELSG32 trial outcomes in the non-trial setting for patients who fit the trial criteria. These data underscore the feasibility and efficacy of MATRix as induction treatment for fit patients in routine practice.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia , Linfoma Difuso de Grandes Células B/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/radioterapia , Terapia Combinada , Comorbidade , Quimioterapia de Consolidação , Irradiação Craniana , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Quimioterapia de Indução , Internacionalidade , Estimativa de Kaplan-Meier , Linfoma Relacionado a AIDS/tratamento farmacológico , Linfoma Relacionado a AIDS/terapia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/radioterapia , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Transplante de Órgãos , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/terapia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Tiotepa/administração & dosagem , Tiotepa/efeitos adversosRESUMO
TBC regimens are considered as "reduced toxicity" and are increasingly employed in pediatric HSCT. In our center, we commonly use the combination of treosulfan-thiotepa-fludarabine and ATG for pediatric non-malignant diseases. As we often observe acute skin toxicities following this conditioning regimen, we conducted a prospective observational study to describe and characterize these toxicities. Fifteen pediatric patients undergoing HSCT for non-malignant diseases who were treated at Hadassah-Hebrew University Medical Center during 2015 were enrolled. A thorough dermatological assessment was done on days 0, 1, 7, and 14 from treatment initiation and included description of cutaneous reactions, measurement of BSA of affected skin, and response to local treatment. All the fifteen enrolled patients developed some degree of acute skin reaction. Cutaneous manifestations were variable and included erythematous patches in inguinal area and genitalia (80%), in neck and axillae (40%), diffuse hyperpigmentation (73%), erosions in inguinal area and buttock (47%), and xerosis and desquamation (40%). Average affected BSA reached 71.8%. Erosions were more prevalent in children younger than 2 years of age. The eruptions resolved without sequela in all patients and did not necessitate treatment other than topical agents. Observed extracutaneous toxicities included oral mucositis (40%), diarrhea (47%), and elevated liver enzymes (47%). TBC combined with thiotepa is highly toxic to the skin with various cutaneous manifestations. The toxicity resolves with no long-term sequela.
Assuntos
Bussulfano/análogos & derivados , Toxidermias/etiologia , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/efeitos adversos , Tiotepa/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Vidarabina/análogos & derivados , Bussulfano/efeitos adversos , Bussulfano/uso terapêutico , Criança , Pré-Escolar , Toxidermias/diagnóstico , Toxidermias/epidemiologia , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/uso terapêutico , Lactente , Masculino , Prognóstico , Estudos Prospectivos , Tiotepa/uso terapêutico , Condicionamento Pré-Transplante/métodos , Vidarabina/efeitos adversos , Vidarabina/uso terapêuticoRESUMO
PURPOSE: Thiotepa is used in high-dose chemotherapy (HDT) before autologous hematopoietic stem cell transplantation (HSCT) to treat solid tumors and hematological malignancies. This Phase 1 study was conducted to establish the pharmacokinetics (PK) of thiotepa in a Japanese population. METHODS: HDT/HSCT was performed in pediatric patients (≥ 2 years) with solid tumors or brain tumors (thiotepa 200 mg/m2/day IV-infused over 24 h on HSCT Days - 12, - 11, - 5, and - 4 and melphalan 70 mg/m2/day IV-infused over 1 h on Days - 11, - 5, and - 4) and adult patients (≥ 16 years) with malignant lymphoma (thiotepa 200 mg/m2/day 2-h IV-infusion on HSCT Days - 4 and - 3 plus busulfan 0.8 mg/kg 2-h IV-infusion every 6 h from HSCT Days - 8 to - 5). Pharmacokinetics of thiotepa were assessed following initial dose. Safety and efficacy were also evaluated. RESULTS: Nine pediatric and 10 adult patients were enrolled. Mean volume of distribution (Vz) of thiotepa normalized with body surface area (BSA) was lower for pediatric patients (16.4 L/m2) compared with adult patients (26.4 L/m2) as expected due to the higher specific surface area of children. Clearance and biological half-life were similar between pediatric and adult patients. Two serious adverse events (cardiac arrest and pulmonary edema) were observed. Survival rate (Day 100 post-HSCT) was 77.8% (95% CI 36.5-93.9%) for pediatric patients and 100% for adult patients. CONCLUSION: Thiotepa elimination was comparable in pediatric and adult patients with cancer. Lower Vz in pediatric compared with adult patients was expected. HDT with thiotepa prior to autologous HSCT was well tolerated. STUDY REGISTRATION: Japic CTI-163433.
Assuntos
Neoplasias Encefálicas , Neoplasias Hematológicas , Linfoma , Tiotepa , Fatores Etários , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/farmacocinética , Superfície Corporal , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Criança , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Feminino , Parada Cardíaca/induzido quimicamente , Parada Cardíaca/diagnóstico , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/patologia , Humanos , Linfoma/tratamento farmacológico , Linfoma/patologia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Avaliação de Processos e Resultados em Cuidados de Saúde , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/diagnóstico , Tiotepa/administração & dosagem , Tiotepa/efeitos adversos , Tiotepa/farmacocinéticaRESUMO
BACKGROUND: Pediatric patients with high-risk, relapsed, or refractory solid tumors have a poor prognosis. We have previously reported a dose-finding experience of high-dose chemotherapy consisting of thiotepa and melphalan ("double-conditioning regimen"). Using doses derived from that study, we have treated patients since 2005. We now report a retrospective review of patients treated by this fixed dose. PROCEDURE: We reviewed 50 patients (median 4 years; range 0-15 years) with high-risk or relapsed/refractory solid tumors treated by this dose-fixed, double-conditioning regimen from April 2005 to May 2014. Doses were thiotepa 800 mg/m2 and melphalan 280 mg/m2 for children ≥2 years of age, and 32 mg/kg and 6 mg/kg, respectively, for children <2 years of age. Further, doses were reduced according to creatinine clearance with poor renal function. RESULTS: Nonhematological toxicity was mainly gastrointestinal-grade 3 mucositis (n = 41) and grade 3-4 diarrhea (n = 10). Neurological, renal, and endothelial cell toxicity and sinusoidal obstruction syndrome were not observed. There were two toxic deaths (interstitial viral pneumonia). This regimen demonstrated antitumor activity against several types of tumors. Although the frequency of gastrointestinal toxicity was high, other severe toxicity was not observed. CONCLUSIONS: Our double-conditioning regimen was very well tolerated and demonstrated antitumor activity. We are moving forward with multi-institutional trials now.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/terapia , Transplante de Células-Tronco de Sangue Periférico , Terapia de Salvação , Condicionamento Pré-Transplante/métodos , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Creatinina/sangue , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Estudos de Viabilidade , Feminino , Seguimentos , Gastroenteropatias/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Lactente , Recém-Nascido , Doenças Pulmonares Intersticiais/etiologia , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Neoplasias/tratamento farmacológico , Pneumonia Viral/etiologia , Estudos Retrospectivos , Risco , Tiotepa/administração & dosagem , Tiotepa/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Transplante AutólogoRESUMO
The prognosis of resistant or relapsing children with neuroblastoma remains very poor, and the search for new therapies is ongoing. In this analysis, we assessed the toxicity of a treosulfan, melphalan, and thiotepa (TMT) regimen in 17 children with recurrent or refractory neuroblastoma who underwent stem cell transplantation (SCT). For allogeneic SCT, fludarabine and antithymocyte globulin were added. The stem cell source was autologous in 8 patients, haploidentical in 8 patients, and a matched unrelated donor in 1 patient. The reported nonhematologic toxicities included grade 3 mucositis, grade 1 to 3 hypertransaminasemia, and in 3 patients, veno-occlusive disease. No neurologic, cardiac, or dermatologic toxicities were observed. The probability of overall survival (OS) in patients with primary resistance was superior to that in patients with relapsed disease (100% versus 22.6%; P = .046). Post-transplantation dinutuximab beta immunotherapy was associated with superior 5-year OS (66.7% versus 11.4%; Pâ¯=â¯.0007). The use of an allogeneic donor, previous autologous SCT with busulfan and melphalan, and pretreatment with high-dose metaiodobenzylguanidine therapy demonstrated no effect on outcomes. In 4 patients, TMT megatherapy alone was enough to achieve complete remission. The TMT conditioning regimen was well tolerated in heavily pretreated patients with neuroblastoma. The manageable toxicity and addition of new anticancer drugs with optional post-SCT immunotherapy or chemotherapy support further trials with the TMT regimen in patients with neuroblastoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neuroblastoma , Transplante de Células-Tronco , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Autoenxertos , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Bussulfano/análogos & derivados , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Neuroblastoma/mortalidade , Neuroblastoma/terapia , Recidiva , Taxa de Sobrevida , Tiotepa/administração & dosagem , Tiotepa/efeitos adversosRESUMO
BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) confined to the central nervous system (CNS) with rising incidence among patients > 65 years. Although elderly patients are able to tolerate aggressive systemic chemotherapy, previous studies have demonstrated inferior outcomes for patients who present with a poor performance status (PS) and older age. Usually, intensive treatment approaches including high-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) are only offered to patients younger than 65-70 years of age. METHODS: This is an open-label, multicentric, non-randomized, single arm phase II trial. We will recruit 51 immuno-competent patients with newly diagnosed PCNSL from 12 German centers. The objective is to investigate the efficacy of age-adapted induction treatment followed by HDT-ASCT. All enrolled patients will undergo induction chemotherapy consisting of 2 cycles of rituximab 375 mg/m2/d (days 0 & 4), methotrexate 3.5 g/m2 (d1), and cytarabine 2 × 2 g/m2/d (d2-3) every 21 days. After 2 cycles of induction chemotherapy, patients achieving at least stable disease will undergo HDT-ASCT with busulfan 3.2 mg/kg/d (days - 7-(- 6)) and thiotepa 5 mg/kg/d (days - 5-(- 4)) followed by autologous stem cell transplantation. The primary endpoint of this study is 1-year progression-free survival (PFS). Secondary endpoints include PFS, overall survival, treatment response and treatment-related morbidities. Minimal follow-up after treatment completion is 12 months. DISCUSSION: Current treatment options for PCNSL have improved over the last years, resulting in the potential to achieve durable remission or cure in patients < 70 years. Age alone may not be the only criterion to select patients for this effective treatment approach and probably many elderly patients are undertreated just because of advanced age. There have been no multicentre trials investigating this curative treatment concept in elderly and fit PCNSL patients so far. We aim to answer whether HDT-ASCT is feasible and effective in fit patients > 65 years with newly-diagnosed PCNSL. TRIAL REGISTRATION: German clinical trials registry DRKS00011932 registered 18 August 2017.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Quimioterapia de Indução/efeitos adversos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Transplante Autólogo/efeitos adversos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos Antineoplásicos , Neoplasias do Sistema Nervoso Central/terapia , Terapia Combinada/efeitos adversos , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/terapia , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Intervalo Livre de Progressão , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Tiotepa/efeitos adversos , Tiotepa/uso terapêuticoRESUMO
Cancer survivorship has increased greatly as therapies have become more advanced and effective. Thus, we must now focus on improving the quality of life of patients after treatment. After chemotherapy, many patients experience chemotherapy-induced cognitive decline, indicating a need to investigate pathologies associated with this condition. In this study, we addressed cognitive impairment after thioTEPA treatment by assessing behavior and assaying cytokine production and the structure of dendrites in the hippocampus. Male mice were given three intraperitoneal injections of thioTEPA. Five weeks later, the mice underwent behavior testing, and brains were collected for Golgi staining and cytokine analysis. Behavior tests included y-maze and Morris water maze and licking behavioral task. Cytokines measured include: IL-1α, IL-1ß, IL-2, IL-3, IL-4, IL-5, IL-10, IL-12p70, MCP-1, TNF-α, GMCSF, and RANTES. We observed decreased memory retention in behavioral tasks. Also, dendritic arborization and length were decreased after chemotherapy treatment. Finally, thioTEPA decreased cytokine production in animals treated with chemotherapy, compared to saline-treated controls. Here, we used a mouse model to correlate the decreases in dendritic complexity and inflammatory cytokine production with cognitive impairment after chemotherapy.
Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Disfunção Cognitiva/induzido quimicamente , Tiotepa/efeitos adversos , Animais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cognição , Citocinas/metabolismo , Injeções Intraperitoneais , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Movimento , Tiotepa/administração & dosagem , Tiotepa/farmacologiaRESUMO
Thiotepa, a highly lipophilic, alkylating agent, and/or its active metabolites may be excreted in part via skin in patients receiving high-dose therapy. We present a case of cutaneous toxicity observed in a 4.5-year-old girl patient with medulloblastoma treated with a high-dose thiotepa conditioning regimen before autologous stem cell transplantation. Skin lesions, as well as their pattern and locations, were evocative of thiotepa toxidermia. After the case herein described, preventive care guidelines were implemented in our unit as from 2014. A retrospective follow-up of 26 pediatric patients receiving thiotepa prior to stem cell transplantation was performed until March 2018. In this series of patients, only one patient experienced cutaneous toxicity as reported herein. Thereafter, only mild cutaneous toxicity was observed, even with double or triple transplantation protocols with high-dose thiotepa. Clear preventive care instructions should be detailed in the Summary of Product Characteristics in order to minimize the cutaneous toxicity of thiotepa.