RESUMEN
OBJECTIVES: Based on a previous phase 1 study, total marrow irradiation (TMI) at 9Gy was added to a myeloablative FluBu4 conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for myeloid malignancies. Here, we report on the long-term toxicity of TMI combined with FluBu4 and compare it to patients who received only FluBu4. METHODS: We retrospectively analyzed 38 consecutive patients conditioned with FluBu4/TMI (n = 15) or FluBu4 (n = 23, control group) who had at least 1 year follow-up post-transplant. The rate of long-term adverse events that have been previously associated with total body irradiation (TBI) was analyzed in the two groups. RESULTS: The baseline characteristics did not differ between the two groups. The control group had a longer median follow-up (71.2 mo) than the TMI group (38.5 mo) (p = .004). The most common adverse events were xerostomia, dental complications, cataracts, or osteopenia and did not differ between the two groups. Cognitive dysfunction or noninfectious pneumonitis, often detected after high dose TBI, were also not different in the two groups (p = .12 and p = .7, respectively). There was no grade 4 adverse event. CONCLUSION: Our results suggest that a conditioning regimen with TMI 9Gy and FluBu4 does not increase long-term adverse events after allogeneic HSCT.
Asunto(s)
Busulfano , Trasplante de Células Madre Hematopoyéticas , Agonistas Mieloablativos , Acondicionamiento Pretrasplante , Trasplante Homólogo , Vidarabina , Humanos , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Vidarabina/análogos & derivados , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Busulfano/efectos adversos , Busulfano/administración & dosificación , Estudios Retrospectivos , Agonistas Mieloablativos/efectos adversos , Agonistas Mieloablativos/uso terapéutico , Agonistas Mieloablativos/administración & dosificación , Irradiación Corporal Total/efectos adversos , Adulto Joven , Estudios de Seguimiento , Médula Ósea/efectos de la radiación , Médula Ósea/efectos de los fármacos , Anciano , AdolescenteRESUMEN
BACKGROUND: The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemoimmunotherapy. Whether ibrutinib-venetoclax and personalization of treatment duration according to measurable residual disease (MRD) is more effective than fludarabine-cyclophosphamide-rituximab (FCR) is unclear. METHODS: In this phase 3, multicenter, randomized, controlled, open-label platform trial involving patients with untreated CLL, we compared ibrutinib-venetoclax and ibrutinib monotherapy with FCR. In the ibrutinib-venetoclax group, after 2 months of ibrutinib, venetoclax was added for up to 6 years of therapy. The duration of ibrutinib-venetoclax therapy was defined by MRD assessed in peripheral blood and bone marrow and was double the time taken to achieve undetectable MRD. The primary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group, results that are reported here. Key secondary end points were overall survival, response, MRD, and safety. RESULTS: A total of 523 patients were randomly assigned to the ibrutinib-venetoclax group or the FCR group. At a median of 43.7 months, disease progression or death had occurred in 12 patients in the ibrutinib-venetoclax group and 75 patients in the FCR group (hazard ratio, 0.13; 95% confidence interval [CI], 0.07 to 0.24; P<0.001). Death occurred in 9 patients in the ibrutinib-venetoclax group and 25 patients in the FCR group (hazard ratio, 0.31; 95% CI, 0.15 to 0.67). At 3 years, 58.0% of the patients in the ibrutinib-venetoclax group had stopped therapy owing to undetectable MRD. After 5 years of ibrutinib-venetoclax therapy, 65.9% of the patients had undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. The risk of infection was similar in the ibrutinib-venetoclax group and the FCR group. The percentage of patients with cardiac serious adverse events was higher in the ibrutinib-venetoclax group than in the FCR group (10.7% vs. 0.4%). CONCLUSIONS: MRD-directed ibrutinib-venetoclax improved progression-free survival as compared with FCR, and results for overall survival also favored ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Linfocítica Crónica de Células B , Neoplasia Residual , Vidarabina , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/patología , Neoplasia Residual/patología , Rituximab/administración & dosificación , Rituximab/efectos adversos , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Factores de Tiempo , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivados , Duración de la TerapiaAsunto(s)
Carcinoma de Células Escamosas , Neoplasias Cutáneas , Humanos , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patología , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/tratamiento farmacológico , Vidarabina/efectos adversosRESUMEN
Hematopoietic stem cell transplant is potentially curative for relapsed/refractory leukemia. However, neurotoxicity is common and has been reported in 11% to 59% of children following hematopoietic stem cell transplant. Most pediatric studies of the neurological effects of hematopoietic stem cell transplant have focused on acute neurotoxicity. Limited information is available for long-term neurotoxicity, particularly those cases that are severe and permanent and caused by conditioning chemotherapy. Here, we report 2 cases of relapsed acute lymphoblastic leukemia that achieved long-term remission by haploidentical hematopoietic stem cell transplant but remained complicated with severe and persistent fludarabine-induced neurotoxicity.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Trasplantes , Humanos , Niño , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Vidarabina/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Acondicionamiento PretrasplanteAsunto(s)
Síndrome de Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Busulfano/efectos adversos , Tiotepa , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Incidencia , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/complicaciones , Vidarabina/efectos adversos , Acondicionamiento Pretrasplante/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Estudios RetrospectivosRESUMEN
We present the case of a 56-year-old female with a diagnosis of acute T-cell lymphoblastic leukemia who received myeloablative conditioning for bone marrow transplant with total body irradiation (TBI) using volumetric modulated arc therapy (VMAT) to the upper body and anterior-posterior/posterior-anterior (AP/PA) open fields to the lower body followed by hematopoietic stem cell transplant. Her clinical course was complicated by high-grade pulmonary toxic effects 55 days after treatment that resulted in death. We discuss the case, planning considerations by radiation oncologists and radiation physicists, and the multidisciplinary medical management of this patient.
Asunto(s)
Radioterapia de Intensidad Modulada , Irradiación Corporal Total , Humanos , Femenino , Persona de Mediana Edad , Irradiación Corporal Total/efectos adversos , Irradiación Corporal Total/métodos , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Vidarabina/efectos adversos , Estudios RetrospectivosRESUMEN
Conditioning with treosulfan and fludarabine (Treo/Flu) has been proven to be feasible and efficient in several types of malignancies before allogeneic hematopoietic stem cell transplantation (allo-HSCT). Given its favorable reduced toxicity profile, we introduced Treo/Flu as conditioning before autologous HSCT (auto-HSCT) in patients with B-cell Non-Hodgkin lymphoma (NHL). The aim of this study was to evaluate the efficacy and safety of Treo/Flu in comparison to TEAM. Fifty-seven patients with NHL received auto-HSCT after conditioning with either Treo/Flu (n = 22) or TEAM (n = 35). All patients achieved sustained engraftment. PFS, EFS and OS were not significant in both groups. Of note is that patients in the Treo/Flu group were less dependent on thrombocyte transfusions (p = 0.0082), significantly older (in median 11 years, p < 0.0001) and suffered less frequently from infectious complications (p = 0.0105), mucositis and stomatitis (p < 0.0001). This study is the first to present efficacy, feasibility, and safety of conditioning with Treo/Flu preceding auto-HSCT in patients with NHL. Since it demonstrated a lack of significant difference in comparison to TEAM conditioning it might be a valuable alternative especially in elderly patients with B-cell NHL and comorbidities. Further evaluation by prospective clinical trials is warranted.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfoma no Hodgkin , Anciano , Busulfano/efectos adversos , Busulfano/análogos & derivados , Humanos , Linfoma no Hodgkin/terapia , Estudios Retrospectivos , Acondicionamiento Pretrasplante/métodos , Trasplante Autólogo , Vidarabina/efectos adversos , Vidarabina/análogos & derivadosRESUMEN
The prognosis for younger patients with relapsed acute myeloid leukaemia (AML) is generally dismal. Allogeneic stem cell transplantation is the preferred therapy for these patients. As part of the UK NCRI AML17 trial, daunorubicin/clofarabine (DClo) was compared with fludarabine, cytarabine, granulocyte colony-stimulating factor with idarubicin (FLAG-Ida) in 311 patients designated high-risk following course one of induction therapy, which has previously been reported. We now report the results of the same randomisation in patients who were refractory to two induction courses or subsequently relapsed. A total of 94 relapsed or refractory AML patients, usually less than 60 years of age and with mainly favourable or intermediate-risk cytogenetics, were randomised to receive up to three courses of DClo or FLAG-Ida, with the aim of proceeding to transplant. Complete remission was achieved in 74% of patients with no difference between the arms. Overall, 57% of patients received a transplant with no difference between the arms, likewise overall survival at five years showed no significant difference (21% for DClo vs. 22% for FLAG-Ida). No patient who did not receive a transplant survived beyond 21months. A stratified analysis including the 311 post course 1 high-risk patients who underwent the same randomisation showed a consistent treatment benefit for FLAG-Ida.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Clofarabina , Idarrubicina , Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad Crónica , Clofarabina/uso terapéutico , Citarabina/uso terapéutico , Daunorrubicina/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Idarrubicina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Reino Unido , Vidarabina/efectos adversosRESUMEN
BACKGROUND: Outcomes for patients with blast-phase chronic myeloid leukaemia are poor. Long-term survival depends on reaching a second chronic phase, followed by allogeneic haematopoietic stem-cell transplantation (HSCT). We investigated whether the novel combination of the tyrosine-kinase inhibitor ponatinib with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) could improve response and optimise allogeneic HSCT outcomes in patients with blast-phase chronic myeloid leukaemia. The aim was to identify a dose of ponatinib, which combined with FLAG-IDA, showed clinically meaningful activity and tolerability. METHODS: MATCHPOINT was a seamless, phase 1/2, multicentre trial done in eight UK Trials Acceleration Programme-funded centres. Eligible participants were adults (aged ≥16 years) with Philadelphia chromosome-positive or BCR-ABL1-positive blast-phase chronic myeloid leukaemia, suitable for intensive chemotherapy. Participants received up to two cycles of ponatinib with FLAG-IDA. Experimental doses of oral ponatinib (given from day 1 to day 28 of FLAG-IDA) were between 15 mg alternate days and 45 mg once daily and the starting dose was 30 mg once daily. Intravenous fludarabine (30 mg/m2 for 5 days), cytarabine (2 g/m2 for 5 days), and idarubicin (8 mg/m2 for 3 days), and subcutaneous granulocyte colony-stimulating factor (if used), were delivered according to local protocols. We used an innovative EffTox design to investigate the activity and tolerability of ponatinib-FLAG-IDA; the primary endpoints were the optimal ponatinib dose meeting prespecified thresholds of activity (inducement of second chronic phase defined as either haematological or minor cytogenetic response) and tolerability (dose-limiting toxicties). Analyses were planned on an intention-to-treat basis. MATCHPOINT was registered as an International Standard Randomised Controlled Trial, ISRCTN98986889, and has completed recruitment; the final results are presented. FINDINGS: Between March 19, 2015, and April 26, 2018, 17 patients (12 men, five women) were recruited, 16 of whom were evaluable for the coprimary outcomes. Median follow-up was 41 months (IQR 36-48). The EffTox model simultaneously considered clinical responses and dose-limiting toxicities, and determined the optimal ponatinib dose as 30 mg daily, combined with FLAG-IDA. 11 (69%) of 16 patients were in the second chronic phase after one cycle of treatment. Four (25%) patients had a dose-limiting toxicity (comprising cardiomyopathy and grade 4 increased alanine aminotransferase, cerebral venous sinus thrombosis, grade 3 increased amylase, and grade 4 increased alanine aminotransferase), fulfilling the criteria for clinically relevant activity and toxicity. 12 (71%) of 17 patients proceeded to allogeneic HSCT. The most common grade 3-4 non-haematological adverse events were lung infection (n=4 [24%]), fever (n=3 [18%]), and hypocalcaemia (n=3 [18%]). There were 12 serious adverse events in 11 (65%) patients. Three (18%) patients died due to treatment-related events (due to cardiomyopathy, pulmonary haemorrhage, and bone marrow aplasia). INTERPRETATION: Ponatinib-FLAG-IDA can induce second chronic phase in patients with blast-phase chronic myeloid leukaemia, representing an active salvage therapy to bridge to allogeneic HSCT. The number of treatment-related deaths is not in excess of what would be expected in this very high-risk group of patients receiving intensive chemotherapy. The efficient EffTox method is a model for investigating novel therapies in ultra-orphan cancers. FUNDING: Blood Cancer UK and Incyte.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mielógena Crónica BCR-ABL Positiva , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Citarabina/efectos adversos , Femenino , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Idarrubicina/efectos adversos , Imidazoles/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Piridazinas/efectos adversos , Vidarabina/efectos adversos , Vidarabina/análogos & derivadosRESUMEN
PURPOSE: Treosulfan and fludarabine (Treo/Flu) were successfully introduced into toxicity-reduced conditioning for SCT. However, the risk of post-SCT relapse remains a matter of concern. We report the results of a novel individual treatment approach with Treo/Flu and cytarabine (Treo/Flu/AraC) conditioning prior to allogeneic SCT in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or myeloproliferative neoplasms (MPN). METHODS: Seventy-seven patients (median age 54 years) at high risk of disease relapse due to unfavorable cytogenetics or failure to achieve complete remission prior to SCT were included. Median follow-up was 3.2 years. RESULTS: The 1-, 2- and 3-year RFS rates were 49.4%, 41.7%, and 37.6% and OS rates were 59.3%, 49.3%, and 45.4%, respectively. Cumulative incidence of NRM was 10% at 100 days, 18.8% at 1 year and 20.1% at 2 years. The cumulative incidence of relapse increased from 31% at 1 year to 38.5% after 3 years. The cumulative incidences of engraftment, chimerism, graft-versus-host disease (GvHD) and toxicities were acceptable and comparable with similar patients conditioned with Treo/Flu or FLAMSA-RIC. CONCLUSION: In conclusion, Treo/Flu/AraC provides tolerable, feasible, and effective conditioning for patients with AML, MDS or MPN, even in advanced disease states. The incidence of NRM and relapse is acceptable in this heavily pre-treated population with high-risk disease. Future research will aim to confirm these initial findings and include a larger number of participants in a prospective trial.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Busulfano/efectos adversos , Busulfano/análogos & derivados , Citarabina/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Trastornos Mieloproliferativos/tratamiento farmacológico , Recurrencia , Estudios Retrospectivos , Acondicionamiento Pretrasplante/métodos , Vidarabina/efectos adversos , Vidarabina/análogos & derivadosRESUMEN
Several PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity. We have recently reported promising efficacy results in treating chronic lymphocytic leukemia (CLL) patients with combination therapy with the PI3Kδγ inhibitor duvelisib and fludarabine cyclophosphamide rituximab (FCR) chemoimmunotherapy, but approximately one-third of patients develop autoimmune toxicity. We show here that duvelisib FCR treatment in an upfront setting modulates both CD4 and CD8 T cell subsets as well as pro-inflammatory cytokines. Decreases in naive and central memory CD4 T cells and naive CD8 T cells occur with treatment, while activated CD8 T cells, granzyme positive Tregs, and Th17 CD4 and CD8 T cells all increase with treatment, particularly in patients with toxicity. Cytokines associated with Th17 activation (IL-17A and IL-21) are also relatively elevated in patients with toxicity. The only CLL feature associated with toxicity was increased priming for apoptosis at baseline, with a significant decrease during the first week of duvelisib. We conclude that an increase in activated CD8 T cells with activation of Th17 T cells, in the context of lower baseline Tregs and greater CLL resistance to duvelisib, is associated with duvelisib-related autoimmune toxicity.
Asunto(s)
Autoinmunidad/efectos de los fármacos , Isoquinolinas/efectos adversos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3/efectos adversos , Purinas/efectos adversos , Linfocitos T/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Citocinas/inmunología , Humanos , Inflamación/inducido químicamente , Inflamación/inmunología , Isoquinolinas/uso terapéutico , Leucemia Linfocítica Crónica de Células B/inmunología , Activación de Linfocitos/efectos de los fármacos , Persona de Mediana Edad , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Purinas/uso terapéutico , Rituximab/efectos adversos , Rituximab/uso terapéutico , Linfocitos T/inmunología , Vidarabina/efectos adversos , Vidarabina/análogos & derivados , Vidarabina/uso terapéuticoRESUMEN
Due to the evolving use of haploidentical donor grafts in hematopoietic cell transplantation, there is increased need to better understand the risks and benefits of using bone marrow versus peripheral blood grafts, as well as how specific pre-transplantation conditioning regimens impact patient safety and treatment outcomes. We performed a retrospective analysis of 38 patients at two centers who underwent haploidentical hematopoietic cell transplantation using fludarabine plus melphalan-based conditioning regimens with post-transplant cyclophosphamide and peripheral blood donor grafts. We observed an unexpectedly high rate of early non-relapse mortality and severe cytokine release syndrome. The poor outcomes with 1-year overall survival of 34%, disease-free survival of 29%, and non-relapse mortality of 34% motivate us to reconsider the appropriateness of the combination of fludarabine and melphalan conditioning with T-cell replete peripheral blood grafts in the setting of haploidentical hematopoietic cell transplant with post-transplant cyclophosphamide.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Melfalán/efectos adversos , Estudios Retrospectivos , Acondicionamiento Pretrasplante/efectos adversos , Vidarabina/efectos adversos , Vidarabina/análogos & derivadosRESUMEN
The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes , Neoplasias Hematológicas , Leucemia Linfocítica Crónica de Células B , Mutación , Mielopoyesis/efectos de los fármacos , Trastornos Mieloproliferativos , Neoplasias Primarias Secundarias , Sulfonamidas , Proteína X Asociada a bcl-2 , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Femenino , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/metabolismo , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/metabolismo , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivados , Proteína X Asociada a bcl-2/antagonistas & inhibidores , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
This study aimed to identify the maximum-tolerated dose (MTD) of cyclophosphamide when combined with bortezomib and fludarabine (B-FC) in a phase 1b trial, and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL (rrMCL). Forty patients were enrolled between April 8, 2011, and October 10, 2015. The MTD of cyclophosphamide was identified to be 250 mg/m2 days 1-2. At a median follow-up of 31.6 months (13.5-47.4), among 32 patients in phase 2, 10 (31%) had a complete response and 13 (41%) had a partial response. The median progression-free survival was 21 months (95% CI 7.3-34.7), and the median overall survival was 32.4 months (95% CI 17.8-47.0). Grade 3-4 hematologic AEs included neutropenia (27%) and thrombocytopenia (39%). The B-FC regimen has satisfactory responses and manageable toxicities in rrMCL patients (ClinicalTrials.gov NCT01322776).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/uso terapéutico , Ciclofosfamida/uso terapéutico , Linfoma de Células del Manto/tratamiento farmacológico , Vidarabina/análogos & derivados , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bortezomib/efectos adversos , Ciclofosfamida/efectos adversos , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Resultado del Tratamiento , Vidarabina/efectos adversos , Vidarabina/uso terapéuticoRESUMEN
BACKGROUND: FLAG ± Ida (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin), is a salvage chemotherapy regimen for relapsed or refractory (R/R) acute myeloid leukemia (AML), with complete remission (CR) rates historically ranging from 52% to 63%. We review the outcomes for patients with R/R AML treated with FLAG ± Ida at the University of California Davis Comprehensive Cancer Center. PATIENTS AND METHODS: Adult patients (≥ 18 years) with R/R AML who received FLAG or FLAG + Ida from January 1, 2012 to October 31, 2016 were identified via chart review. Outcomes evaluated were CR, CR with incomplete hematologic recovery (CRi), overall response rate, overall survival (OS), relapse-free survival, and adverse events. RESULTS: Forty-two patients were included. The median age was 52 years (range, 23-73 years), and 57% were male. Sixteen (38.1%) patients had relapsed disease, and 26 (61.9%) had refractory disease. Most (n = 35; 83.3%) patients had European LeukemiaNet intermediate-risk AML. Responses were CR in 20 (47.6%) and CRi in 6 (14.3%). The median OS was 10 months (range, 0.8-51 months), and the median relapse-free survival was 12 months (range, 1-51 months) for responders. The median OS for patients who achieved CR was not reached, and the estimated 48-month survival rate was 56%. The median OS after CRi or no response was 3.47 and 2.17 months, respectively. The median OS was not significantly different when censored for stem cell transplant following chemotherapy, nor with use/deferral of idarubicin. The most common adverse effects were pancytopenia and infection. CONCLUSION: Patient outcomes after treatment with FLAG ± Ida for R/R AML remain similar to prior reports, confirming its role as a salvage regimen for these patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Leucemia Mieloide Aguda/terapia , Recurrencia Local de Neoplasia/terapia , Terapia Recuperativa/métodos , Vidarabina/análogos & derivados , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Instituciones Oncológicas/estadística & datos numéricos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Idarrubicina/administración & dosificación , Idarrubicina/efectos adversos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Pancitopenia/inducido químicamente , Pancitopenia/epidemiología , Estudios Retrospectivos , Terapia Recuperativa/estadística & datos numéricos , Tasa de Supervivencia , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Adulto JovenRESUMEN
Prognosis for relapsed or refractory (R/R) acute myeloid leukemia (AML) despite salvage therapy is dismal. This phase I dose-escalation trial assessed the safety and preliminary clinical activity of selinexor, an oral exportin-1 (XPO1) inhibitor, in combination with FLAG-Ida in younger R/R AML patients. The aim was to find the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD). Fourteen patients were included, and selinexor dosage was 60 mg (3 patients), 80 mg (3 patients), and 100 mg (7 patients) weekly. No dose-limiting toxicities were reported. Grade ≥3 non-hematologic adverse events (AEs) occurred in 78.6% of patients. Two patients were non MTD evaluable due to early death, and overall, 3 out of 14 patients (21.4%) had fatal AEs. Five out of 12 (42%) response and MTD evaluable patients achieved a complete remission (CR; n=4) or CR with incomplete hematologic recovery (CRi, n=1), and 4 patients (33%) subsequently underwent allogeneic transplantation. The median overall survival (OS) and event-free survival (EFS) were 6.0 (range 0.9-19.3) and 1.1 months (range 0.7-19.3), respectively. Using selinexor 100 mg/weekly, CR/CRi rate of 66.7%, OS 13.6 months (range, 1.6-19.3), and EFS 10.6 months (range, 0.9-19.3). At last follow-up, 3 patients were alive. Selinexor 100 mg/weekly with FLAG-Ida combination in R/R AML showed acceptable tolerability and efficacy, establishing the RP2D of this regimen in future clinical trials. ClinicalTrials.gov Identifier: NCT03661515.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Hidrazinas/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Triazoles/uso terapéutico , Vidarabina/análogos & derivados , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Citarabina/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Hidrazinas/administración & dosificación , Hidrazinas/efectos adversos , Idarrubicina/administración & dosificación , Idarrubicina/efectos adversos , Idarrubicina/uso terapéutico , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Resultado del Tratamiento , Triazoles/administración & dosificación , Triazoles/efectos adversos , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/uso terapéuticoRESUMEN
Patients with chronic lymphocytic leukaemia (CLL) have an increased risk of new malignancies. However, limited data have been published about the impact of CLL treatment on this risk. Here we followed a Danish population-based cohort of CLL patients for risks of new malignancies. Patients in the Danish CLL registry (2008-2017) were included. Up to 50 CLL-free matched comparators were identified. First-line treatment was categorized into four groups; bendamustine, chlorambucil, fludarabine or other. Patients were followed from CLL diagnosis for individual types of malignancy. Adjusted hazard ratios (HR) for new malignancies and 95% confidence intervals (95% CI) were calculated. Overall, 4286 CLL patients and 214 150 controls developed 594 and 20 565 new malignancies respectively. Risk of new malignancies was increased for CLL patients. Chemotherapy treatment was registered for 1064 (25%) patients with CLL. Chemotherapy was associated with increased HR (1·51, 95% CI: 1·3-1·8) of any new malignancy. Specifically, fludarabine was associated with an increased risk of myelodysplastic syndrome (MDS) (HR 4·93, 95% CI: 1·2-19·8). Patients with CLL are at increased risk of other haematological and solid malignancies compared to the general population. Chemotherapy exposure is associated with increased risk of second malignancies and fludarabine is associated with increased risk of MDS.
Asunto(s)
Antineoplásicos/efectos adversos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Síndromes Mielodisplásicos/inducido químicamente , Neoplasias Primarias Secundarias/inducido químicamente , Anciano , Antineoplásicos/uso terapéutico , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/uso terapéutico , Clorhidrato de Bendamustina/efectos adversos , Clorhidrato de Bendamustina/uso terapéutico , Clorambucilo/efectos adversos , Clorambucilo/uso terapéutico , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Síndromes Mielodisplásicos/epidemiología , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/patología , Sistema de Registros , Medición de Riesgo , Análisis de Supervivencia , Vidarabina/efectos adversos , Vidarabina/análogos & derivados , Vidarabina/uso terapéuticoRESUMEN
Therapeutic options used to be very limited for treatment-naïve elderly/comorbid patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) before the introduction of chemo-immunotherapy. Because dose-reduced fludarabine-based regimens yielded promising results, the Czech CLL Study Group initiated a prospective observational study to assess safety and efficacy of low-dose fludarabine and cyclophosphamide combined with rituximab (FCR) in elderly/comorbid patients. Between March 2009 and July 2012, we enrolled 107 patients considered ineligible for full-dose FCR (median age, 70 years; median Cumulative Illness Rating Scale score, 5; median creatinine clearance, 69 ml/min). Notably, 77% patients had unfavourable biological prognosis [unmutated immunoglobulin heavy-chain variable-region gene (IGHV), 74%; deletion 17p, 9%). Fludarabine was reduced to 12 mg/m2 intravenously (iv) or 20 mg/m2 orally on days 1-3 and cyclophosphamide to 150 mg/m2 iv/orally on days 1-3. Grade 3-4 neutropenia occurred in 56% of the patients, but there were serious infections in only 15%. The median progression-free survival was 29 months, but was markedly longer in patients with mutated IGHV (median 53 months), especially in absence of del 11q or 17p (median 74 months). Low-dose FCR is a well-tolerated and effective first-line regimen for selected elderly/comorbid patients with CLL/SLL with favourable biology. The study was registered at clinicaltrials.gov (NCT02156726).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , República Checa/epidemiología , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Rituximab/administración & dosificación , Rituximab/efectos adversos , Tasa de Supervivencia , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivadosRESUMEN
A head-to-head comparison of outcomes of unrelated donor allogeneic peripheral blood stem cell transplantation for AML between reduced intensity conditioning (RIC) and myeloablative conditioning (MAC) regimens using thymoglobulin for GVHD prophylaxis is limited. We evaluated outcomes of 122 AML patients who received either busulfan (Bu)/fludarabine (Flu)/low-dose total body irradiation (TBI) as RIC (n = 64, 52%) or Bu/Flu as MAC (n = 58, 48%), and thymoglobulin 4.5 mg/kg total dose between day - 3 to - 1 for GVHD prophylaxis. Grades III-IV acute GVHD (aGVHD) was lower with Bu/Flu/TBI compared with Bu/Flu (6.2% vs 26.1%, p = 0.009). At 1 year, Bu/Flu/TBI was associated with similar chronic GVHD (41.2% vs 44.8%, p = 0.75), OS (61.9% vs 56.9%, p = 0.69), relapse rate (29.9% vs 20.7%, p = 0.24), relapse-free survival (52.8% vs 50%, p = 0.80), non-relapse mortality (17.4% vs 29.3%, p = 0.41), and GVHD-free relapse-free survival (24.2% vs 27.5%, p = 0.80) compared with Bu/Flu. Multivariable analysis did not reveal any difference in outcomes between both regimens. In summary, thymoglobulin at 4.5 mg/kg did not have any adverse impact on survival when used with RIC regimen. Both Bu/Flu/TBI and Bu/Flu conditioning regimens yielded similar survival.
Asunto(s)
Suero Antilinfocítico/uso terapéutico , Busulfano/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Inmunosupresores/uso terapéutico , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/uso terapéutico , Trasplante de Células Madre de Sangre Periférica , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Anciano , Aloinjertos , Busulfano/efectos adversos , Femenino , Enfermedad Injerto contra Huésped/etiología , Humanos , Infecciones/epidemiología , Depleción Linfocítica , Masculino , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Agonistas Mieloablativos/efectos adversos , Supervivencia sin Progresión , Estudios Retrospectivos , Linfocitos T , Tacrolimus/uso terapéutico , Resultado del Tratamiento , Donante no Emparentado , Vidarabina/efectos adversos , Vidarabina/uso terapéutico , Irradiación Corporal TotalRESUMEN
The manageable toxicity profile of obinutuzumab (GA101; G) alone or with chemotherapy in first-line (1L; fit and non-fit) and relapsed/refractory (R/R) patients with chronic lymphocytic leukaemia (CLL) was established in the primary analysis of the Phase IIIb GREEN trial (Clinicaltrials.gov: NCT01905943). The final analysis (cut-off, 31 January 2019) is reported here. Patients received G (1000 mg) alone (G-mono; fit and non-fit patients) or with chemotherapy [fludarabine and cyclophosphamide (FC; fit patients); chlorambucil (non-fit patients); bendamustine (any patient)]. Study endpoints were safety (primary) and efficacy (secondary). Subgroup analyses were performed on prognostic biomarkers in 1L CLL. Overall, 630 patients received 1L and 341 received R/R CLL treatment. At the final analysis, no new safety signals were observed [Grade ≥ 3 adverse events (AEs): 1L 82·7%, R/R 84·5%; serious AEs: 1L 58·1%, R/R 62·5%]. Neutropenia (1L 50·5%, R/R 53·4%) and thrombocytopenia (1L 14·6%, R/R 19·1%) were the most common Grade 3-5 AEs. G-mono-, G-bendamustine and G-FC-treated patients with unmutated immunoglobulin heavy chain trended towards shorter progression-free survival. Achievement of minimal residual disease negativity was greatest in 1L patients treated with G-FC. In this final analysis of the GREEN trial, the safety profile of G was consistent with current risk management strategies. Biomarker analyses supported efficacy in the specific subgroups.