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1.
Blood ; 139(18): 2747-2757, 2022 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-35511184

RESUMEN

High-dose melphalan (HDM) and transplantation are recommended for eligible patients with multiple myeloma. No other conditioning regimen has proven to be more effective and/or safer. We previously reported in a phase 2 study that bortezomib can safely and effectively be combined with HDM (Bor-HDM), with a 32% complete response (CR) rate after transplantation. These data supported a randomized phase 3 trial. Randomization was stratified according to risk and response to induction: 300 patients were enrolled, and 154 were allocated to the experimental arm (ie, arm A) with bortezomib (1 mg/m2 intravenously [IV]) on days -6, -3, +1, and +4 and melphalan (200 mg/m2 IV) on day -2. The control arm (ie, arm B) consisted of HDM alone (200 mg/m2 IV). There were no differences in stringent CR + CR rates at day 60 posttransplant (primary end point): 22.1% in arm A vs 20.5% in arm B (P = .844). There were also no differences in undetectable minimum residual disease rates: 41.3% vs 39.4% (P = .864). Median progression-free survival was 34.0 months for arm A vs 29.6 months for arm B (adjusted HR, 0.82; 95% CI, 0.61-1.13; P = .244). The estimated 3-year overall survival was 89.5% in both arms (hazard ratio, 1.28; 95% CI, 0.62-2.64; P = .374). Sixty-nine serious adverse events occurred in 18.7% of Bor-HDM-treated patients (vs 13.1% in HDM-treated patients). The proportion of grade 3/4 AEs was similar within the 2 groups (72.0% vs 73.1%), mainly (as expected) blood and gastrointestinal disorders; 4% of patients reported grade 3/4 or painful peripheral neuropathy in arm A (vs 1.5% in arm B). In this randomized phase 3 study, a conditioning regimen with Bor-HDM did not improve efficacy end points or outcomes compared with HDM alone. The original trial was registered at www.clinicaltrials.gov as #NCT02197221.


Asunto(s)
Melfalán , Mieloma Múltiple , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bortezomib/efectos adversos , Humanos , Melfalán/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/etiología , Trasplante Autólogo
2.
Blood ; 137(26): 3616-3628, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-33763699

RESUMEN

Continuous lenalidomide-dexamethasone (Rd)-based regimens are among the standards of care in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. The oral proteasome inhibitor ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. In the double-blind, placebo-controlled TOURMALINE-MM2 trial, transplant-ineligible NDMM patients were randomized to ixazomib 4 mg (n = 351) or placebo (n = 354) plus Rd. After 18 cycles, dexamethasone was discontinued and treatment was continued using reduced-dose ixazomib (3 mg) and lenalidomide (10 mg) until progression/toxicity. The primary endpoint was progression-free survival (PFS). Median PFS was 35.3 vs 21.8 months with ixazomib-Rd vs placebo-Rd, respectively (hazard ratio [HR], 0.830; 95% confidence interval, 0.676-1.018; P = .073; median follow-up, 53.3 and 55.8 months). Complete (26% vs 14%; odds ratio [OR], 2.10; P < .001) and ≥ very good partial response (63% vs 48%; OR, 1.87; P < .001) rates were higher with ixazomib-Rd vs placebo-Rd. In a prespecified high-risk cytogenetics subgroup, median PFS was 23.8 vs 18.0 months (HR, 0.690; P = .019). Overall, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With ixazomib-Rd vs placebo-Rd, 88% vs 81% of patients experienced grade ≥3 TEAEs, 66% vs 62% serious TEAEs, and 35% vs 27% TEAEs resulting in regimen discontinuation; 8% vs 6% died on study. Addition of ixazomib to Rd was tolerable with no new safety signals and led to a clinically meaningful PFS benefit of 13.5 months. Ixazomib-Rd is a feasible option for certain patients who can benefit from an all-oral triplet combination. This trial was registered at www.clinicaltrials.gov as #NCT01850524.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Mieloma Múltiple , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos de Boro/administración & dosificación , Compuestos de Boro/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Estudios de Seguimiento , Glicina/administración & dosificación , Glicina/efectos adversos , Glicina/análogos & derivados , Humanos , Lenalidomida/administración & dosificación , Lenalidomida/efectos adversos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Tasa de Supervivencia
3.
Am J Hematol ; 98(2): 264-271, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36588407

RESUMEN

Familial forms of monoclonal gammopathy, defined as multiple myeloma (MM) or Monoclonal Gammopathy of Undetermined Significance (MGUS), are relatively infrequent and most series reported in the literature describe a limited number of families. MM rarely occurs in a familial context. MGUS is observed much more commonly, which can in some cases evolve toward full-blown MM. Although recurrent cytogenetic abnormalities have been described in tumor cells of sporadic cases of MM, the pathogenesis of familial MM remains largely unexplained. In order to identify genetic factors predisposing to familial monoclonal gammopathy, the Intergroupe Francophone du Myélome identified 318 families with at least two confirmed cases of monoclonal gammopathy. There were 169 families with parent/child pairs and 164 families with cases in at least two siblings, compatible with an autosomal transmission. These familial cases were compared with sporadic cases who were matched for age at diagnosis, sex and immunoglobulin isotype, with 10 sporadic cases for each familial case. The gender distribution, age and immunoglobulin subtypes of familial cases were unremarkable in comparison to sporadic cases. With a median follow-up of 7.4 years after diagnosis, the percentage of MGUS cases having evolved to MM was 3%. The median overall survival of the 148 familial MM cases was longer than that of matched sporadic cases, with projected values of 7.6 and 16.1 years in patients older and younger than 65 years, respectively. These data suggest that familial cases of monoclonal gammopathy are similar to sporadic cases in terms of clinical presentation and carry a better prognosis.


Asunto(s)
Gammopatía Monoclonal de Relevancia Indeterminada , Mieloma Múltiple , Paraproteinemias , Niño , Humanos , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Paraproteinemias/genética , Paraproteinemias/complicaciones , Mieloma Múltiple/patología , Pronóstico , Aberraciones Cromosómicas
4.
J Oncol Pharm Pract ; 29(5): 1172-1177, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36067063

RESUMEN

INTRODUCTION: Two phase 3 studies demonstrated superior efficacy of intravenous daratumumab (DARA IV) plus bortezomib/melphalan/prednisone (ALCYONE) or lenalidomide/dexamethasone (Rd; MAIA) versus standard-of-care regimens for transplant-ineligible newly diagnosed multiple myeloma. In these studies, patients could switch from DARA IV to subcutaneous daratumumab (DARA SC) while receiving daratumumab monotherapy in ALCYONE (as of Cycle 11) or daratumumab plus Rd in MAIA. The phase 3 COLUMBA study demonstrated noninferiority of DARA SC to DARA IV. DARA SC reduced administration time, allowing patients to spend less time in healthcare settings, a relevant practical consideration for patient care in the COVID-19 pandemic/settings of limited healthcare resources. METHODS: DARA SC 1800 mg was administered every 4 weeks, per approved dosing schedules. We evaluated safety and patient-reported experience (ALCYONE only) among patients who switched from DARA IV to DARA SC. RESULTS: Fifty-seven patients in ALCYONE and 135 in MAIA switched to DARA SC. Three (2.2%; MAIA) patients reported injection-site reactions, all of which were mild. No infusion-related reactions occurred with DARA SC. In ALCYONE, >80% of patients preferred DARA SC over DARA IV. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 5.3% of patients in ALCYONE and 25.9% in MAIA; one (0.7%; MAIA) patient experienced a TEAE with an outcome of death. CONCLUSION: For transplant-ineligible newly diagnosed multiple myeloma, DARA SC (monotherapy/with Rd) was safe and preferred over DARA IV. ClinicalTrials.gov, NCT02195479/NCT02252172.


Asunto(s)
COVID-19 , Mieloma Múltiple , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bortezomib/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Pandemias
5.
Haematologica ; 106(12): 3100-3106, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34047178

RESUMEN

The aim of this study was to characterize a large series of 154 patients with acute promyelocytic leukemia (median age, 53 years; range, 18-90 years) and evaluate real-life outcome after up-front treatment with arsenic trioxide and all-trans retinoic acid. All patients were included in the prospective NAPOLEON registry (NCT02192619) between 2013 and 2019. The acute promyelocytic leukemia was de novo in 91% (n=140) and therapy-related in 9% (n=14); 13% (n=20) of the patients were older than 70 years. At diagnosis bleeding/hemorrhage was present in 38% and thrombosis in 3%. Complete remission was achieved in 152 patients (99%), whereas two patients (1%) experienced induction death within 18 days after starting therapy. With a median follow-up of 1.99 years (95% confidence interval: 1.61-2.30 years) 1-year and 2-year overall survival rates were 97% (95% confidence interval: 94-100%) and 95% (95% confidence interval: 91-99%), respectively. Age above 70 years was associated with a significantly shorter overall survival (P<0.001) compared to that of younger patients. So far no relapses have been observed. Six patients (4%) died in complete remission at a median of 0.95 years after diagnosis (range, 0.18-2.38 years). Our data confirm the efficiency and durability of arsenic trioxide and all-trans retinoic acid therapy in the primary management of adults with low-/intermediate-risk acute promyelocytic leukemia in the real-life setting, irrespective of age.


Asunto(s)
Trióxido de Arsénico , Leucemia Promielocítica Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Trióxido de Arsénico/uso terapéutico , Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Persona de Mediana Edad , Estudios Prospectivos , Inducción de Remisión , Medición de Riesgo , Resultado del Tratamiento , Tretinoina/uso terapéutico , Adulto Joven
7.
Haematologica ; 101(3): 363-70, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26659916

RESUMEN

Renal impairment is associated with poor prognosis in myeloma. This analysis of the pivotal phase 3 FIRST trial examined the impact of renally adapted dosing of lenalidomide and dexamethasone on outcomes of patients with different degrees of renal impairment. Transplant-ineligible patients not requiring dialysis were randomized 1:1:1 to receive continuous lenalidomide and dexamethasone until disease progression (n=535) or for 18 cycles (72 weeks; n=541), or melphalan, prednisone, and thalidomide for 12 cycles (72 weeks; n=547). Follow-up is ongoing. Patients were grouped by baseline creatinine clearance into no (≥ 80 mL/min [n=389]), mild (≥ 50 to < 80 mL/min [n=715]), moderate (≥ 30 to < 50 mL/min [n=372]), and severe impairment (< 30 mL/min [n=147]) subgroups. Continuous lenalidomide and dexamethasone therapy reduced the risk of progression or death in no, mild, and moderate renal impairment subgroups vs. melphalan, prednisone, and thalidomide therapy (HR = 0.67, 0.70, and 0.65, respectively). Overall survival benefits were observed with continuous lenalidomide and dexamethasone treatment vs. melphalan, prednisone, and thalidomide treatment in no or mild renal impairment subgroups. Renal function improved from baseline in 52.6% of lenalidomide and dexamethasone-treated patients. The safety profile of continuous lenalidomide and dexamethasone was consistent across renal subgroups, except for grade 3/4 anemia and rash, which increased with increasing severity of renal impairment. Continuous lenalidomide and dexamethasone treatment, with renally adapted lenalidomide dosing, was effective for most transplant-ineligible patients with myeloma and renal impairment. Trial registration: ClinicalTrials.gov (NCT00689936); EudraCT (2007-004823-39). Funding: Intergroupe Francophone du Myélome and the Celgene Corporation.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dexametasona/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Insuficiencia Renal/tratamiento farmacológico , Talidomida/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Creatinina/sangre , Progresión de la Enfermedad , Esquema de Medicación , Femenino , Humanos , Lenalidomida , Masculino , Melfalán/uso terapéutico , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/mortalidad , Prednisona/uso terapéutico , Pronóstico , Estudios Prospectivos , Insuficiencia Renal/complicaciones , Insuficiencia Renal/diagnóstico , Insuficiencia Renal/mortalidad , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Talidomida/uso terapéutico , Resultado del Tratamiento
8.
Am J Hematol ; 91(4): 366-70, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26689746

RESUMEN

Intravascular hemolysis in Paroxysmal nocturnal hemoglobinuria (PNH) can effectively be controlled with eculizumab, a humanized monoclonal antibody that binds complement protein C5. We report here a retrospective comparison study between 123 patients treated with eculizumab in the recent period (>2005) and 191 historical controls (from the French registry). Overall survival (OS) at 6 years was 92% (95%CI, 87 to 98) in the eculizumab cohort versus 80% (95%CI 70 to 91) in historical controls diagnosed after 1985 (HR 0.38 [0.15 to 0.94], P = 0.037). There were significantly fewer thrombotic events (TEs) in the group of patients treated with eculizumab (4% [1-10]) as compared to the historical cohort (27% [20-34]). However, we found that TEs may still occur after the initiation of eculizumab treatment and that previous TEs still have a negative impact on survival. Evolutions to myelodysplastic syndrome or acute leukemia were similar in both cohorts. There was less evolution to aplastic anemia in the treatment group. In multivariate analysis, absence of a previous TE and treatment with eculizumab were associated with a better OS. Treatment with eculizumab improves overall survival in classic PNH patients without increasing the risk of clonal evolution.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Hemoglobinuria Paroxística/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados/farmacología , Complemento C5/antagonistas & inhibidores , Femenino , Estudios de Seguimiento , Hemoglobinuria Paroxística/diagnóstico , Hemoglobinuria Paroxística/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Resultado del Tratamiento
10.
Genes Chromosomes Cancer ; 53(1): 106-16, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24249260

RESUMEN

Mantle cell lymphoma (MCL) is usually an aggressive disease. However, a few patients do have an "indolent" evolution (iMCL) defined by a long survival time without intensive therapy. Many studies highlight the prognostic role of additional genetic abnormalities, but these abnormalities are not routinely tested for and do not yet influence the treatment decision. We aimed to evaluate the prognostic impact of these additional abnormalities detected by conventional cytogenetic testing, as well as their relationships with the clinical characteristics and their value in identifying iMCL. All consecutive MCL cases diagnosed between 1995 and 2011 at four institutions were retrospectively selected on the basis of an informative karyotype with a t(11;14) translocation at the time of diagnosis. A total of 125 patients were included and followed for an actual median time of 35 months. The median overall survival (OS) and survival without treatment (TFS) were 73.7 and 1.3 months, respectively. In multivariable Cox models, a high mantle cell lymphoma international prognostic index score, a complex karyotype, and blastoid morphology were independently associated with a shortened OS. Spleen enlargement, nodal presentation, extra-hematological involvement, and complex karyotypes were associated with shorter TFS. A score based on these factors allowed for the identification of "indolent" patients (median TFS 107 months) from other patients (median TFS: 1 month). In conclusion, in this multicentric cohort of MCL patients, a complex karyotype was associated with a shorter survival time and allowed for the identification of iMCL at the time of diagnosis.


Asunto(s)
Cromosomas Humanos/genética , Cariotipo , Linfoma de Células del Manto/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Femenino , Humanos , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia
11.
Am J Hematol ; 89(4): 399-403, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24375467

RESUMEN

Gemtuzumab ozogamicin (fGO), a humanized anti-CD33 monoclonal antibody linked to calicheamicin in combination with intensive chemotherapy gives high response rates in adult acute myeloid leukemia (AML) patients in relapse. However, reduced intensity chemotherapy in combination with fractionated GO has not been tested in aged relapsing patients. Patients from our institution with CD33+ AML aged 55 years or more in first late relapse (≥ 6 months) were proposed participation in a GO compassionate use program. Induction therapy consisted in fractionated GO (fGO; 3 mg/m², days 1, 4, 7) with standard-dose cytarabine (200 mg/m² /day, 7 days). Patients were consolidated with two courses of GO and intermediate dose cytarabine. Twenty-four patients (median age 68 years) received fGO with cytarabine. Median follow-up was 42 months. The response rate was 75%, including complete remission (CR) in 16 patients and CR with incomplete platelet recovery (CRp) in two patients. Two-year overall survival (OS) was 51% (95% CI: 28-69) and 2 years relapse-free survival (RFS) was 51% (95%CI: 25-72). Duration of second CR (CR2) was longer than first CR (CR1) in 9 out of 18 patients. Minimal residual disease (MRD) was negative in evaluable patients in CR2, particularly in NPM1 mutated cases. Toxicity was in line with that of the same fractionated single agent GO schedule. Fractionated GO with low intensity chemotherapy produced high response rates and prolonged CR2 in aged AML patients in first late relapse.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Terapia Recuperativa , Anciano , Aminoglicósidos/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Ensayos de Uso Compasivo , Quimioterapia de Consolidación , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Filgrastim , Gemtuzumab , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Inmunofenotipificación , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Aguda/tratamiento farmacológico , Leucemia Mielomonocítica Aguda/genética , Masculino , Metilprednisolona/administración & dosificación , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutropenia/prevención & control , Nucleofosmina , Proteínas Recombinantes/uso terapéutico , Inducción de Remisión , Trombocitopenia/sangre , Trombocitopenia/inducido químicamente
12.
Clin Hematol Int ; 6(3): 22-27, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39050939

RESUMEN

The therapeutic management of patients with multiple myeloma (MM) is complex. Despite substantial advances, MM remains incurable, and management involves cycles of treatment response, disease relapse, and further therapy. Currently, evidence to support the therapeutic decision is limited. Thus, the EMMY longitudinal, real-world study was designed to annually assess therapeutic management of MM in France to provide evidence to support physicians. During an annual prespecified 3-month recruitment period, eligible patients will be identified from their medical records. Adults aged ≥18 years diagnosed with symptomatic MM and requiring systemic treatment will be eligible. The primary objective, the evolution of MM therapeutic management, will be described, as well as the impact on the following outcomes: time-to-next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). The study plans to recruit 5000 patients over 6 years: 700 to 900 patients annually. EMMY is a unique opportunity to collect real-world data to describe the evolving MM therapeutic landscape and record outcomes in France. These data will provide annual snapshots of various aspects of MM management. This knowledge will provide physicians with real-life, evidence-based data for therapeutic decision-making and ultimately improve treatment for MM patients.

13.
Nat Med ; 30(8): 2235-2241, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38830994

RESUMEN

CD38-targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) that are transplant ineligible (TI) and is considered the best standard of care (SOC). To improve current SOC, we evaluated the added value of weekly bortezomib (V) to isatuximab plus lenalidomide and dexamethasone (IsaRd versus Isa-VRd). This Intergroupe Francophone of Myeloma phase 3 study randomized 270 patients with NDMM that were TI, aged 65-79 years, to IsaRd versus Isa-VRd arms. The primary endpoint was a minimal residual disease (MRD) negativity rate at 10-5 by next-generation sequencing at 18 months from randomization. Key secondary endpoints included response rates, MRD assessment rates, survival and safety. The 18-month MRD negativity rates at 10-5 were reported in 35 patients (26%, 95% confidence interval (CI) 19-34) in IsaRd versus 71 (53%, 95% CI 44-61) in Isa-VRd (odds ratio for MRD negativity 3.16, 95% CI 1.89-5.28, P < 0.0001). The MRD benefit was consistent across subgroups at 10-5 and 10-6, and was already observed at month 12. The proportion of patients with complete response or better at 18 months was higher with Isa-VRd (58% versus 33%; P < 0.0001), as was the proportion of MRD negativity and complete response or better (37% versus 17%; P = 0.0003). At a median follow-up of 23.5 months, no difference was observed for survival times (immature data). The addition of weekly bortezomib did not significantly affect the relative dose intensity of IsaRd. Isa-VRd significantly increased MRD endpoints, including the 18-month negativity rate at 10-5, the primary endpoint, compared with IsaRd. This study proposes Isa-VRd as a new SOC for patients with NDMM that are TI. ClinicalTrials.gov identifier: NCT04751877 .


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Dexametasona , Lenalidomida , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Bortezomib/administración & dosificación , Bortezomib/uso terapéutico , Lenalidomida/administración & dosificación , Lenalidomida/uso terapéutico , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Anciano , Masculino , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasia Residual , Resultado del Tratamiento
14.
Blood ; 118(23): 6030-6, 2011 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-21976672

RESUMEN

The primary objective of this 2-part phase 1/2 study was to determine the maximum-tolerated dose (MTD) of the potent and selective Aurora B kinase inhibitor barasertib (AZD1152) in patients with newly diagnosed or relapsed acute myeloid leukemia (AML). Part A determined the MTD of barasertib administered as a continuous 7-day infusion every 21 days. In part B, the efficacy of barasertib was evaluated at the MTD. In part A, 32 patients were treated with barasertib 50 mg (n = 3), 100 mg (n = 3), 200 mg (n = 3), 400 mg (n = 4), 800 mg (n = 7), 1200 mg (n = 6), and 1600 mg (n = 6). Dose-limiting toxicities (stomatitis/mucosal inflammation events) were reported in the 800 mg (n = 1), 1200 mg (n = 1), and 1600 mg (n = 2) groups. The MTD was defined as 1200 mg. In part B, 32 patients received barasertib 1200 mg. In each part of the study, 8 of 32 patients had a hematologic response according to Cheson AML criteria. The most commonly reported grade ≥ 3 events were febrile neutropenia (n = 24) and stomatitis/mucosal inflammation (n = 16). We concluded that the MTD of barasertib is 1200 mg in patients with relapsed or newly diagnosed AML. Toxicity was manageable and barasertib treatment resulted in an overall hematologic response rate of 25%. This study is registered at www.ClinicalTrials.gov as NCT00497991.


Asunto(s)
Leucemia Mieloide Aguda/tratamiento farmacológico , Organofosfatos , Inhibidores de Proteínas Quinasas , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quinazolinas , Anciano , Anciano de 80 o más Años , Aurora Quinasa B , Aurora Quinasas , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Organofosfatos/administración & dosificación , Organofosfatos/efectos adversos , Organofosfatos/farmacocinética , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética , Recurrencia , Índice de Severidad de la Enfermedad
15.
Pan Afr Med J ; 41: 338, 2022.
Artículo en Francés | MEDLINE | ID: mdl-35865841

RESUMEN

IgD myeloma is an extremely rare haemopathy with severe clinical presentation. It can be confused with non-secretory or free light chain myeloma. We here report the case of a 72-year old female patient presenting with bone pain and diffuse ecchymosis and deterioration of her general condition. Laboratory tests showed monoclonal gammopathy associated with severe acute renal failure and low total protein (TP) (48%) with factor X deficiency. Etiological assessment confirmed the diagnosis of IgD lambda myeloma stage IIIb, according to Durie and Salmon, International Staging System (ISS) score III unfavorable cytogenetics. Patient's outcome was favorable after treatment with proteasome inhibitor, anti-CD 38 and corticosteroid therapy. Adequate treatment of IgD myeloma, using new therapeutic approaches and hematopoietic stem cell autotransplantation, can improve the prognosis.


Asunto(s)
Deficiencia del Factor X , Mieloma Múltiple , Anciano , Deficiencia del Factor X/complicaciones , Femenino , Humanos , Inmunoglobulina D , Cadenas Ligeras de Inmunoglobulina , Cadenas lambda de Inmunoglobulina/metabolismo , Mieloma Múltiple/complicaciones , Mieloma Múltiple/diagnóstico
16.
Clin Cancer Res ; 25(14): 4224-4230, 2019 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-31053600

RESUMEN

PURPOSE: Carfilzomib is a novel generation proteasome inhibitor. The Carmysap trial demonstrated that twice-weekly KMP (carfilzomib, melphalan, prednisone) might challenge the MPV (melphalan, prednisone, bortezomib) standard. We sought to study KMP weekly, allowing to increase carfilzomib's dose with maintained efficacy and improved safety profile. PATIENTS AND METHODS: IFM2012-03, a phase I multicenter study of KMP weekly in elderly patients with newly diagnosed multiple myeloma (eNDMM), aimed to determine the MTD of carfilzomib. Carfilzomib was given intravenously at 36, 45, 56, and 70 mg/m2/day on days 1, 8, 15, and 22 with melphalan and prednisone, for nine 35-day induction cycles, followed by carfilzomib maintenance for 1 year. Three dose-limiting toxicities (DLT) determined MTD at the lower dose. RESULTS: Thirty eNDMMs were treated, 6 per cohort at 36, 45, and 56 mg/m2 and 12 at 70 mg/m². There was one DLT at 36 mg/m2 (lymphopenia), one at 45 mg/m2 (lysis syndrome), two at 56 mg/m2 (cardiac insufficiency and febrile neutropenia), and two at 70 mg/m2 (vomiting and elevated liver enzymes). The safety profile was acceptable; however, specific attention must be paid to the risk of cardiovascular events, especially for elderly patients. The overall response rate was 93.3%, with 46.6% complete response. CONCLUSIONS: The MTD dose of carfilzomib was 70 mg/m2 in this KMP weekly study in eNDMM. Response rates, and especially CR rate, were remarkable in this population, and would benefit from being assessed in a larger-scale study. The IFM2012-03 study demonstrated that the MTD of carfilzomib weekly is 70 mg/m2 in eNDMM, and 56 mg/m2 for patients older than 75 years. Carfilzomib used weekly in combination has a good efficacy and safety profile in eNDMM.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Esquema de Medicación , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Dosis Máxima Tolerada , Melfalán/administración & dosificación , Mieloma Múltiple/patología , Oligopéptidos/administración & dosificación , Seguridad del Paciente , Prednisona/administración & dosificación , Criterios de Evaluación de Respuesta en Tumores Sólidos , Tasa de Supervivencia , Resultado del Tratamiento
17.
Haematologica ; 93(12): 1806-13, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18838471

RESUMEN

BACKGROUND: There is a need for standardization of treatment decisions in older patients with acute myeloid leukemia. The aim of the present study was to analyze the decisional value of poor risk factors in 416 elderly patients treated in the ALFA-9803 trial in order to derive a decisional index. DESIGN AND METHODS: Standard multivariate analysis was used to identify risk factors for overall survival. Risk factors were then considered as good decision tools if associated with a frequency >10% and a false positive rate <10% in predicting overall survival as poor as observed after low-dose cytarabine therapy (25% survival or less at 12 months). RESULTS: Among six independent risk factors (age, performance status, white blood cell count, hematopoietic cell transplantation comorbidity index, infection at baseline, and cytogenetics), cytogenetics was the only potent, independent decision tool. High hematopoietic cell transplantation comorbidity index scores or infections were found too rarely to guide further decisions. The three other factors (age, performance status, and white cell count) needed to be combined to provide a good specificity. The proposed decisional index, therefore, included high-risk cytogenetics and/or the presence of at least two of the following criteria: age > or =75 years, performance status > or =2, and white cell count > or =50 x 10(9)/L. This simple two-class decisional index, which was validated in an independent patient set, enabled us to discriminate 100 patients (24%) who had an estimated overall survival of only 19% at 12 months, with a good 9% false positive rate. CONCLUSIONS: We propose waiting for cytogenetic information before making treatment decisions in elderly patients with acute myeloid leukemia. Those patients with unfavorable cytogenetics, as well as patients with at least two of the following features, age > or =75 years, performance status > or =2, and white cell count > or =50 x 10(9)/L, should not be considered for standard intensive chemotherapy (ClinicalTrials.gov identifier: NCT00363025).


Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/diagnóstico , Guías de Práctica Clínica como Asunto , Factores de Edad , Anciano , Anciano de 80 o más Años , Ensayos Clínicos como Asunto , Análisis Citogenético , Daunorrubicina/uso terapéutico , Toma de Decisiones , Femenino , Humanos , Idarrubicina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Recuento de Leucocitos , Masculino , Selección de Paciente , Factores de Riesgo , Análisis de Supervivencia
18.
Leuk Lymphoma ; 59(7): 1659-1665, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29179634

RESUMEN

Although the tyrosine kinase inhibitor (TKI) era has brought great improvement in outcome in chronic myelogenous leukemia (CML), prognosis of accelerated phase or myeloid blast crisis patients or of de novo Philadelphia chromosome-positive acute myeloid leukemia remains poor. We conducted a retrospective study on patients with advanced phase disease treated with a TKI and azacytidine. Sixteen patients were eligible. Median age was 64.9 years, the median number of previous therapies was 2.5 lines, and median follow-up was 23.1 months. Hematologic response (HR) rate was 81.3%. Median overall survival (OS), event free survival and relapse-free survival (RFS) were 31.5, 23.3, and 32.2 months, respectively. All except one patient were treated as out-patients after the first cycle. Five patients were bridged to allogenic hematopoietic stem cells transplant. The combination of a TKI and azacytidine is a safe and efficient regiment for patients with CML patients in advanced phases.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azacitidina/administración & dosificación , Biomarcadores , Terapia Combinada , Análisis Citogenético , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide de Fase Crónica/diagnóstico , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/administración & dosificación , Trasplante Homólogo , Resultado del Tratamiento
19.
Eur Heart J Cardiovasc Imaging ; 18(4): 392-401, 2017 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-28064155

RESUMEN

AIMS: We sought to assess whether global longitudinal strain (GLS) measured early during treatment with anthracyclines (at a cumulative dose of 150 mg/m2) can predict subsequent alterations in left ventricular ejection fraction. METHODS AND RESULTS: Eighty-six patients with Hodgkin's disease, non-Hodgkin's lymphoma, or acute leukaemia and receiving anthracyclines were prospectively included. Patients underwent complete echocardiography on four occasions: baseline (V1); after reaching a cumulative dose of 150 mg/m2 (V2); end of treatment (V3); and 1 year follow-up (V4). Six patients developed cardiotoxicity, defined as a decrease in left ventricular ejection fraction of >10 percentage points, to a value <53%, at V4. GLS measured at V1 and V2 was significantly lower in the cardiotoxicity group vs. the controls (P = 0.042 and P = 0.01, respectively). Compared with GLS at V1, GLS obtained at V2 provided incremental predictive information and appeared to be the strongest predictor of cardiotoxicity (area under the receiver-operating-characteristic curve, 0.82). At a threshold of -17.45% for GLS measured at V2, the sensitivity and specificity of detecting cardiotoxicity were 67% (95% confidence interval 33-100) and 97% (95% confidence interval 94-100), respectively. CONCLUSION: GLS greater than -17.45%, obtained after 150 mg/m2 of anthracycline therapy, is an independent predictor of future anthracycline-induced cardiotoxicity. These findings should encourage physicians to perform echocardiography earlier during treatment with anthracyclines.


Asunto(s)
Antraciclinas/efectos adversos , Cardiotoxicidad/diagnóstico por imagen , Neoplasias Hematológicas/tratamiento farmacológico , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/diagnóstico por imagen , Adulto , Anciano , Antraciclinas/uso terapéutico , Cardiotoxicidad/etiología , Cardiotoxicidad/fisiopatología , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Ecocardiografía , Femenino , Neoplasias Hematológicas/patología , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Variaciones Dependientes del Observador , Selección de Paciente , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Volumen Sistólico/efectos de los fármacos
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