RESUMEN
Very scarce data exist about outcomes of relapsed multiple myeloma patients who have failed proteasome inhibitor, immunomodulatory drug, anti-CD38 monoclonal antibody and therapies targeting B-cell maturation antigen (BCMA) (Quad-class exposed [QCE]). In this retrospective single-centre study, we determined progression-free survival (PFS) and overall survival (OS) from anti-BCMA failure in 45 QCE patients. Seven (16%) patients received antibody-drug conjugate, 20 (44%) bispecific antibodies and 18 (40%) CAR-T cell. Thirty patients (67%) received ≥1 subsequent line of treatment. PFS was 4.4 months (95% CI = 2.4-12.5) and OS 6.3 months (95% CI = 3.9-14.4). Having an adverse prognosis, QCE myeloma patients remain an unmet medical need.
Asunto(s)
Anticuerpos Biespecíficos , Inmunoconjugados , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Estudios Retrospectivos , Pronóstico , Anticuerpos Biespecíficos/uso terapéutico , Antígeno de Maduración de Linfocitos B , Inmunoterapia AdoptivaRESUMEN
The presence of donor Vγ9Vδ2 T-cells after haploidentical hematopoietic stem cell transplant (h-HSCT) has been associated with improved disease-free survival. These cells kill tumor cells in a non-MHC restricted manner, do not induce graft-versus-host disease (GVHD), and can be generated by stimulation with zoledronic acid (ZA) in combination with interleukin-2 (IL-2). This monocentric phase I, open-label, dose-escalating study (ClinicalTrials.gov: NCT03862833) aimed at evaluating the safety and possibility to generate Vγ9Vδ2 T-cells early after h-HSCT. It applied a standard 3 + 3 protocol to determine the maximum tolerated dose (MTD) of increasing low-doses of IL-2 (5 days [d] per week, 4 weeks) in combination with a single dose of ZA, starting both the first Monday after d + 15 posttransplant. Vγ9Vδ2 T-cell monitoring was performed by multiparameter flow cytometry on blood samples and compared with a control cohort of h-HSCT recipients. Twenty-six patients were included between April 2019 and September 2022, 16 of whom being ultimately treated and seven being controls who received h-HSCT only. At the three dose levels tested, 1, 0, and 1 dose-limiting toxicities were observed. MTD was not reached. A significantly higher number of Vγ9Vδ2 T-cells was observed during IL-2 treatment compared with controls. In conclusion, early in vivo generation of Vγ9Vδ2 T-cells is feasible after h-HSCT by using a combination of ZA and repeated IL-2 infusions. This study paves the way to a future phase 2 study, with the hope to document lesser posttransplant relapse with this particular adaptive immunotherapy.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Interleucina-2 , Ácido Zoledrónico , Linfocitos T/patología , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Trasplante de Células MadreRESUMEN
Superior rates of deep molecular response (DMR) have been reported with the combination of tyrosine kinase inhibitors and pegylated-interferon-alpha (Peg-IFN) in patients with newly diagnosed chronic phase-chronic myeloid leukaemia (CP-CML). In this setting, this study investigated the efficacy and safety of dasatinib combined to Peg-IFN-α2b (Dasa-PegIFN, NCT01872442). A total of 79 patients (age ≤65 years) started dasatinib; 61 were eligible for Peg-IFNα-2b add-on therapy at month 3 for a maximum 21-months duration. Dasatinib was continued thereafter. The primary endpoint was the cumulative rate of molecular response 4.5 log (MR4.5 ) by 12 months. The results are reported for the 5-year duration of the study. Grade 3 neutropenia was frequent with the combination but did not induce severe infection (one of grade 3). Other adverse events were generally low grade (4% of grade 3-4) and expected. Seventy-nine per cent and 61% of patients continued the Peg-IFN until months 12 and 24, respectively. Overall, at these time points, MR4.5 rates were 25% and 38%, respectively. Thereafter, 32% and 46% of patients achieved a sustained (≥2 years) MR4.5 or MR4 , respectively. This work established the feasibility and high rates of achievement of early and sustained DMR (a prerequisite for treatment-free-remission) with dasatinib and Peg-IFNα-2b combination as initial therapy.
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Interferón-alfa , Leucemia Mieloide de Fase Crónica , Humanos , Anciano , Dasatinib/efectos adversos , Interferón-alfa/efectos adversos , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Polietilenglicoles/efectos adversos , Resultado del TratamientoRESUMEN
Discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia is feasible in clinical practice based on recently published international recommendations. Nevertheless, factors predictive of molecular recurrence have not been fully elucidated and long-term follow-up of patients enrolled in clinical studies are required in order to update knowledge on discontinuation attempts particularly in terms of the safety and durability of treatment-free remission (TFR). In the current study, we updated results from the STIM2 study in the light of the consensual criterion of molecular recurrence reported in different international recommendations. Among the 199 patients included in the perprotocol study, 108 patients lost a major molecular response. With a median follow-up of 40.8 months (5.5-111 months), the probability of treatment-free remission was 43.4% [36.3-50.4] at 5 years, 40.9% [32.8-47.3] at 7 years and 34.5% [25.6- 43.3] at 9 years. Molecular recurrence occurred between 0 to 6 months, 6 to 24 months and after 24 months in 75 patients (69%), 15 patients (14%) and 18 patients (17%), respectively. Notably, the kinetics of molecular recurrence differed significantly between these three subgroups with a median time from loss of MR4 (BCR::ABL1 IS≤0.01%) to loss of major molecular response of 1, 7 and 22 months, respectively. Predictive factors of molecular recurrence differed according to the time of occurrence of the molecular recurrence. Durations of imatinib treatment and deep molecular response as well as BCR::ABL1/ABL1 levels at cessation of tyrosine kinase inhibitor treatment, as quantified by reverse transcriptase droplet digital polymerase chain reaction, are involved in molecular recurrence occurring up to 24 months but not beyond. (ClinicalTrial. gov Identifier NCT#0134373).
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Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide de Fase Crónica , Humanos , Proteínas de Fusión bcr-abl/genética , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inducción de Remisión , Molécula de Interacción Estromal 2 , Resultado del TratamientoRESUMEN
Dasatinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for patients with chronic myeloid leukaemia (CML). Dasatinib 100 mg per day is associated with an increased risk of pleural effusion (PlEff). We randomly evaluated whether therapeutic drug monitoring (TDM) may reduce dasatinib-associated significant adverse events (AEs) by 12 months (primary endpoint). Eligible patients started dasatinib at 100 mg per day followed by dasatinib (C)min assessment. Patients considered overdosed [(C)min ≥ 3 nmol/l) were randomised between a dose-reduction strategy (TDM arm) and standard of care (control arm). Out of 287 evaluable patients, 80 patients were randomised. The primary endpoint was not met due to early haematological AEs occurring before effective dose reduction. However, a major reduction in the cumulative incidence of PlEff was observed in the TDM arm compared to the control arm (4% vs. 15%; 11% vs. 35% and 12% vs. 39% at one, two and three years, respectively (P = 0·0094)). Molecular responses were superimposable in all arms. Dasatinib TDM during treatment initiation was feasible and resulted in a significant reduction of the incidence of PlEff in the long run, without impairing molecular responses. (NCT01916785; https://clinicaltrials.gov).
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Antineoplásicos/uso terapéutico , Dasatinib/uso terapéutico , Monitoreo de Drogas , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Derrame Pleural/inducido químicamente , Inhibidores de Proteínas Quinasas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Dasatinib/administración & dosificación , Dasatinib/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Derrame Pleural/prevención & control , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
Next-generation sequencing (NGS) is used to investigate the presence of somatic mutations. The utility of incorporating routine sequencing to guide diagnosis and therapeutic decisions remains unclear. We report the findings of an observational, multicenter study that aimed to assess the impact of somatic mutation testing by NGS in a reallife setting of chronic myeloid malignancies. A total of 177 patients were enrolled, partitioned into two overlapping groups. In group A (n=94), the indication was to search for clonal hematopoiesis, in a context of suspected myelodysplastic syndrome or myeloproliferative neoplasia. In group B (n=95), the theranostic impact of somatic mutations was studied. A panel of 34 genes was used on DNA extracted from blood or bone marrow samples. Within group A, the detection of clonal hematopoiesis supported the diagnosis of chronic myeloid malignancies for 31 patients while the absence of clonal hematopoiesis ruled out the suspected diagnosis in 47 patients. Within group B, NGS identified prognostically relevant somatic mutations in 32 patients, which had a therapeutic impact in 18 cases. By determining the presence or absence of somatic mutations, the application of NGS in daily practice was found to be useful for an integrated final diagnosis in 83% of the patients. Moreover, the search for somatic mutations had a prognostic impact that led to treatment modification in 19% of the cases. This study outlines the fact that adequate implementation of new investigations may have a significant positive medico-economic impact by enabling appropriate management of patients.
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Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Neoplasias , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , PronósticoRESUMEN
BACKGROUND: The impact of acute graft versus host disease (GVHD) on survivals for patients receiving a haploidentical allogeneic stem-cell transplant (Allo-SCT) with peripheral blood stem-cells (PBSC) complemented by post-transplant cyclophosphamide (PTCY) is ill-known. MATERIAL AND METHODS: This retrospective study included 131 patients who received a PBSC haplograft in order to precise the impact of acute GVHD on outcomes. There were 78 males and 53 females and the median age for the whole cohort was 59 years (range: 20-71). Thirty-five patients were allografted for a lymphoid disease and 96 for a myeloid malignancy, including 67 patients with acute myeloid leukemia (AML). RESULTS: The cumulative incidence (CI) of day 100 grade 2-4 and 3-4 acute GVHD was 43.4 + 4.6% and 16.7 + 3.4%, respectively. The 2-year CI of moderate/severe chronic GVHD was 10.1 + 2.8%. The only factor affecting the occurrence of GVHD was GVHD prophylaxis. Indeed, CI of day 100 grade 2-4 (but not grade 3-4) acute GVHD was significantly reduced when adding anti-thymoglobulin (ATG) to PTCY. However, in multivariate analysis, grade 2 acute GVHD was significantly associated with better disease-free (HR: 0.36; 95%CI: 0.19-0.69, p = .002) and overall (HR: 0.35; 95%CI: 0.1-0.70, p = .003) survivals. The same results were observed when considering only AML patients. CONCLUSION: Acute grade 2 GVHD is a factor of good prognosis after PBSC haplotransplant with PTCY. Further and larger studies are needed to clarify the complex question of GVHD prophylaxis in the setting of haplo-transplant, especially that of combining ATG and PTCY.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Células Madre de Sangre Periférica , Adulto , Anciano , Ciclofosfamida , Femenino , Enfermedad Injerto contra Huésped/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Adulto JovenRESUMEN
The influence of peripheral blood stem cell (PBSC) graft cell contents after transplant with post-transplant cyclophosphamide (PTCY) remains unclear. Here, we retrospectively report on a cohort of 77 adults who received a Baltimore-based reduced-intensity conditioning regimen either with fludarabine (n = 40) or clofarabine (n = 37) and PTCY. With a median follow-up of 29.2 months, [2-]year overall (OS), disease-free (DFS), and GVHD/relapse-free survival (GRFS) rates were 62.8%, 51%, and 36.7%, respectively. The incidence of grades [2-]4 acute GVHD was significantly higher in patients transplanted with a haplodonor (n = 56), at 57.1% vs 19% (p = 0.006). PBSC graft cell contents (CD45+, CD34+, and CD3+ cells) had no impact on any outcome. Considering immune reconstitution until 1 year, only monocytes were above the normal range (as early as day + 30) during the first year post-transplant. In multivariate analysis, an older donor (> 45 years) and a high/very high disease risk index were independently associated with lower OS. A higher monocyte count (> median) at day + 90 was also associated with better OS, DFS, and GRFS. Donor/recipient CMV status matching was independently associated with GRFS. In conclusion, our data support the fact that there is no need to manipulate the graft before infusion in the particular context of PBSC/PTCY Baltimore-based allotransplant.
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Antígenos CD34/sangre , Complejo CD3/sangre , Ciclofosfamida/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Supervivencia de Injerto/fisiología , Trasplante de Células Madre Hematopoyéticas/tendencias , Humanos , Inmunosupresores/administración & dosificación , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Acondicionamiento Pretrasplante/tendencias , Resultado del Tratamiento , Adulto JovenRESUMEN
Follicular lymphoma (FL) is an indolent non-Hodgkin's lymphoma with heterogeneous outcomes. Progression or relapse of FL within 2 years (so-called POD24) after diagnosis is associated with a poor outcome for patients treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) in clinical trials. POD24 needs further validation before it can be used as a relevant endpoint to assess treatment efficacy. In the present retrospective monocentric study, we investigated the predictive value of POD24 in a cohort of grade 1, 2, or 3a FL patients treated in our institution (Nantes Medical University, France) and registered in our local database. We investigated the nature of treatment lines, patients' outcomes, and the prognostic value of POD24. Between 2007 and 2016, 317 patients were included. After first-line therapy, 60 patients relapsed within 2 years (POD24-pos cohort), and 254 patients did not relapse within 2 years (PO24-neg cohort). Thirty-three patients died, and 34 patients had an aggressive transformation. The median follow-up is 59.9 months (1.6-395.5). The median PFS is 59.9 months. Overall survival (OS) at 1 year, 3 years, and 5 years is 98.4% [97.0-99.8], 95.1% [92.6-97.6], and 92.5% [89.3-95.9], respectively. The 5-year OS was statistically lower for POD24-pos patients (82% [71.9-93.5]) than for POD24-neg patients (93.3% [88.98-97.8]) (p = 10-5). In multivariate analyses, transformation was predictive of OS, and PS (≥ 1) was predictive of POD24. POD24 is predictive of a worse OS and may be recommended as a relevant endpoint in clinical trials and in real life in particular for patients with advanced disease.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores de Tumor , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamiento farmacológico , Rituximab/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Estudios de Cohortes , Ciclofosfamida/administración & dosificación , Progresión de la Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Francia/epidemiología , Humanos , Linfoma Folicular/mortalidad , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Valor Predictivo de las Pruebas , Prednisona/administración & dosificación , Pronóstico , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
The impact of early fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET-CT) status on survival after allogeneic transplantation for lymphoma is poorly reported. This retrospective study included all adult Hodgkin lymphoma (HL) or non-Hodgkin lymphoma(NHL) patients (>18 years old) who benefited from FDG PET-CT before (within 1 month) and/or early (+3 months and within +6 to 9 months) after allogeneic stem cell transplantation in our institution between 2005 and 2015 and who were still without documented progression or relapse at the time of the FDG PET-CT. All FDG PET-CT were reviewed by a nuclear medicine expert in hematology and restaged according to the Deauville scale. FDG-PET CT was considered positive when the uptake was higher than liver background (Deauville score ≥ 4). The primary objective was to study the impact of pre- and post-transplant FDG PET-CT on lymphoma-free survival (LFS) and overall survival (OS). Inclusion criteria were fulfilled for 103 patients (69 men; median age, 51.6 years old; range, 22 to 67). Diagnoses were high-grade NHL (nâ¯=â¯47), low-grade NHL (nâ¯=â¯6), T cell lymphoma (nâ¯=â¯34), and HL (nâ¯=â¯16). More than half of the patients were in complete remission at the time of transplant (nâ¯=â¯56). A reduced-intensity conditioning regimen was applied in most cases (nâ¯=â¯90). With a median follow-up of 49.5 months (range, 6 to 140.5) for alive patients, median 3-year OS and LFS were, respectively, 81% (range, 71% to 87%) and 65% (range, 54% to 74%) for the entire cohort. In multivariate analysis, positive FDG PET-CT at 3 months was the strongest independent factor significantly associated with poorer LFS (hazard ratio, 9.22; 95% confidence interval, 1.88 to 645.2; Pâ¯=â¯.006). FDG PET-CT positivity at 3 months appears to be highly predictive of LFS in patients after allogeneic transplantation and may help to guide strategies to prevent relapse. These results need to be validated prospectively.
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Trasplante de Células Madre Hematopoyéticas/métodos , Linfoma/diagnóstico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Adulto , Anciano , Femenino , Fluorodesoxiglucosa F18 , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Linfoma/mortalidad , Linfoma/patología , Linfoma/terapia , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Recurrencia , Estudios Retrospectivos , Análisis de Supervivencia , Factores de Tiempo , Trasplante Homólogo , Adulto JovenRESUMEN
Clofarabine-based reduced-intensity conditioning (RIC) regimens are well-established schedules for allograft in patients with myeloid malignancies. A retrospective study was conducted including all adults allografted in our department with such a regimen and disease with the aim to assess whether or not the donor type (matched sibling [MSD], matched unrelated [MUD], or haploidentical [haplo]) impacted outcomes. Between October 2009 and February 2018, 118 patients met the inclusion criteria. Thirty-six, 55, and 27 patients received a graft from an MSD, MUD, or haplo donor, respectively. Peripheral blood stem cells (PBSCs) were the source of graft for all patients. The median age of the entire cohort was 62 years (range, 20 to 73), and the median follow-up was 31 months (range, 4.5 to 106). All patients engrafted except 1 haplo recipient. Neutrophils (>.5 × 109/L) and platelets (50 × 109/L) recoveries were significantly delayed in the haplo group (Pâ¯=â¯.0003 and P < .0001) compared with MSD and MUD. Acute grades II to IV or III to IV graft-versus-host disease (GVHD) incidences were similar between the 3 groups as well as the incidence of moderate or severe chronic GVHD. Also, similar 2-year overall survival (OS; 64.7% versus 73.9% versus 60.2%, Pâ¯=â¯.39), disease-free survival (DFS; 57.7% versus 70.9% versus and 53.6%, Pâ¯=â¯.1), and GVHD relapse-free survival (37.9% versus 54.3% versus 38.9%, Pâ¯=â¯.23) were observed between MSD versus MUD versus haplo groups. The same was true when considering only acute myeloid leukemia (AML) cases. In multivariate analysis the type of donor remained independent of outcomes in this series, whereas myelodysplastic syndrome (versus AML), high disease risk index, and older donor (≥50 years) were associated with lower OS and DFS. These data suggest that haplo donors are an acceptable alternative for patients receiving a clofarabine-based RIC PBSC allograft for myeloid malignancies who lack an MSD or a MUD.
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Clofarabina/administración & dosificación , Neoplasias Hematológicas , Leucemia Mieloide Aguda , Hermanos , Acondicionamiento Pretrasplante , Donante no Emparentado , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Humanos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante HaploidénticoRESUMEN
OBJECTIVE: This study was designed to assess the impact on outcomes of early soluble Fms-like tyrosine kinase 3 ligand concentrations (sFLc) in patients receiving an allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). METHODS: This was a prospective monocentric study including all allo-HSCT patients included in the previous FLAM/FLAL study (Peterlin et al., 2019). Blood samples collected before the start of conditioning then post-transplant were frozen, stored and tested by ELISA. The parameters considered were hematopoietic recoveries, Leukemia Free Survival and Overall Survival, acute and chronic GVHD, grade 3 or 4 acute and/or extensive chronic GVHD-free and relapse-free survival (GRFS). RESULTS: Forty-one patients were included, a total of 179 samples were assayed for sFLc. There was no impact of sFLc levels (<=median vs>â¯median) on acute and chronic GVHD incidences, LFS, OS nor GRFS. CONCLUSION: At variance with induction results for AML (Peterlin et al., 2019) endogenous sFLc do not appear to be a prognostic marker at the time of or after allo-HSCT. Even though the results are negatives, this is, to the best of our knowledge, the only prospective series specifically addressing the question of sFLc impact after allo-HSCT in acute leukemias.
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Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/terapia , Proteínas de la Membrana/sangre , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Solubilidad , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Pomalidomide dexamethasone is a standard of care for relapsed multiple myeloma (MM) patients who received at least two prior lines of therapy, including both lenalidomide and proteasome inhibitors (PI). We report here a real-life single-center series of 49 consecutive patients with relapsed and refractory MM treated with the triplet pomalidomide cyclophosphamide dexamethasone (PCD) combination. The median of prior lines of therapy was 3 and all patients were previously exposed to proteasome inhibitors and lenalidomide. The overall response rate was 76%, including 27% very good partial response or better. With a median follow-up of 16 months, the median progression-free survival (PFS) was 7.3 months and the median overall survival was not reached. Regarding safety, most frequent toxicity was hematologic, including 37% grade 3-4 cytopenias. Nine patients (18%) discontinued therapy due to adverse event. Our study confirms that PCD combination is feasible and results in favorable response rate and PFS in comparison with pomalidomide dexamethasone alone.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Terapia Recuperativa , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Evaluación de Medicamentos , Sustitución de Medicamentos , Femenino , Enfermedades Hematológicas/inducido químicamente , Humanos , Estimación de Kaplan-Meier , Lenalidomida/uso terapéutico , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Inhibidores de Proteasas/uso terapéutico , Recurrencia , Estudios Retrospectivos , Talidomida/administración & dosificación , Talidomida/efectos adversos , Talidomida/análogos & derivadosRESUMEN
The anti-CD38 monoclonal antibody daratumumab is approved as a single agent for the treatment of patients with relapsed and refractory multiple myeloma (RRMM) who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMID), or who are double refractory to a PI and an IMID. To date, no real-life data on the efficacy and tolerance of daratumumab in this setting are available. We report here the results of a single-center series of 41 RRMM patients treated with single-agent daratumumab outside clinical trials. Patients received a median number of 4 prior therapies. All patients were previously exposed to PI and IMID and all patients were refractory to the last line of therapy. Most patients presented with high-risk characteristics, including 24% adverse cytogenetics (del17p/t(4,14)), 31% extramedullary disease and 12% circulating plasmacytosis at time of daratumumab therapy. The overall response rate was 24%, including 5% very good partial response or better. After a median follow-up of 6.5 months, all patients experienced disease relapse. The median progression-free survival was 1.9 months. At the time of disease progression, 44% of patients did not receive subsequent therapy. The median overall survival was 6.5 months. No new safety signal was identified. These real-life results revealed modest efficacy of single-agent daratumumab in advanced patients with RRMM in comparison with data from clinical trials.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Terapia Recuperativa , ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Evaluación de Medicamentos , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Glicoproteínas de Membrana/antagonistas & inhibidores , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Supervivencia sin Progresión , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: The ultimate goal of chronic myeloid leukemia management in the tyrosine kinase inhibitor (TKI) era for patients who obtain deep molecular responses is maintaining a durable off-treatment response after treatment discontinuation; this situation is called treatment-free remission (TFR). Knowledge accumulated during the last 10 years justifies moving TFR strategies from research to clinical practice. METHODS: Twenty experts from the French Chronic Myeloid Leukemia Study Group (France Intergroupe des Leucémies Myéloïdes Chroniques), including 17 hematologists, 2 molecular biologists, and 1 cytogeneticist, critically reviewed published data with the goal of developing evidence-based recommendations for TKI discontinuation in clinical practice. RESULTS: Clinically relevant questions were addressed, including the selection of candidate patients (with known prognostic factors for outcomes taken into account), detailed monitoring procedures during the treatment-free phase, a definition of relapse requiring therapy resumption, and monitoring after treatment reintroduction. CONCLUSIONS: This work presents consensus statements with the aim of guiding physicians and biologists by means of pragmatic recommendations for safe TKI discontinuation in daily practice. Cancer 2018;124:2956-63. © 2018 American Cancer Society.
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Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Hematología/normas , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Oncología Médica/normas , Recurrencia Local de Neoplasia/diagnóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Factores de Edad , Consenso , Francia , Proteínas de Fusión bcr-abl/sangre , Proteínas de Fusión bcr-abl/aislamiento & purificación , Proteínas de Fusión bcr-abl/metabolismo , Hematología/métodos , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Oncología Médica/métodos , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/prevención & control , Educación del Paciente como Asunto , Selección de Paciente , Pronóstico , Inducción de Remisión/métodos , Resultado del Tratamiento , Espera Vigilante/normas , Adulto JovenRESUMEN
Late complications (LC) and quality of life (QOL) were analyzed in 110 adult patients who underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) and were alive for more than 2 years after allo-SCT. Overall survival of these patients was 93% (95% confidence interval [CI], 88% to 99%) and 81% (95% CI, 71% to 94%) at 5 and 10 years, respectively. The primary cause of death was a recurrence of primary malignancy. With a median follow-up of 4.6 years (range, 2 to 12.1), chronic graft-versus-host disease (cGVHD) was the most prevalent late effect, with a cumulative incidence of 66% (95% CI, 57% to 74%) at 10 years. Cardiovascular complications were the most prevalent LC with a cumulative incidence of 47% (95% CI, 35% to 59%), followed by pulmonary complications with a cumulative incidence of 33% (95% CI, 21% to 46%) and renal impairment with a cumulative incidence of 34% (95% CI, 25% to 43%) at 10 years. Secondary malignancies occurred with a cumulative incidence of 11% (95% CI, 5% to 20%) at 10 years. In this series, 61 patients (55%) responded to QOL survey. With the use of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 and Functional Assessment of Cancer Therapy-Bone Marrow Transplant questionnaires, most of the patients reported good to excellent QOL and patients with cGVHD had significantly lower QOL than patients without cGVHD. In conclusion, QOL after RIC is comparable to that seen after myeloablative conditioning, while the natural history of LC after RIC appears to be different from that described in the standard myeloablative setting, warranting further research in this field.
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Trasplante de Células Madre Hematopoyéticas/efectos adversos , Calidad de Vida , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Enfermedades Cardiovasculares/etiología , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Enfermedades Pulmonares/etiología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/etiología , Calidad de Vida/psicología , Encuestas y Cuestionarios , Sobrevivientes/psicología , Acondicionamiento Pretrasplante/efectos adversos , Trasplante Homólogo , Adulto JovenAsunto(s)
Vacuna BNT162/uso terapéutico , COVID-19/prevención & control , Adulto , Anciano , Aloinjertos , Anticuerpos Antivirales/inmunología , Formación de Anticuerpos , Vacuna BNT162/administración & dosificación , COVID-19/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trasplante de Órganos , Estudios Retrospectivos , SARS-CoV-2/inmunología , Trasplante de Células Madre , Trasplante Homólogo , Adulto JovenAsunto(s)
Anticuerpos Antivirales/biosíntesis , Vacuna BNT162/inmunología , COVID-19/prevención & control , Inmunoglobulina G/biosíntesis , Inmunoterapia Adoptiva , SARS-CoV-2/inmunología , Adulto , Anciano , Antígenos Virales/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Vacuna BNT162/efectos adversos , Productos Biológicos/uso terapéutico , Terapia Combinada , Femenino , Fiebre/etiología , Trasplante de Células Madre Hematopoyéticas , Humanos , Inmunización Secundaria , Huésped Inmunocomprometido , Inmunogenicidad Vacunal , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/terapia , Masculino , Persona de Mediana Edad , Dolor/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfocitos T/uso terapéutico , Receptores Quiméricos de Antígenos/uso terapéutico , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunación , Adulto JovenRESUMEN
Despite persistence of leukemic stem cells, patients with chronic myeloid leukemia who achieve and maintain deep molecular responses may successfully stop the tyrosine kinase inhibitor imatinib. However, questions remain unanswered regarding the biological basis of molecular relapse after imatinib cessation. In IMMUNOSTIM, we monitored 51 patients from the French Stop IMatinib trial for peripheral blood T cells and natural killer cells. Molecular relapse-free survival at 24 months was 45.1% (95% CI: 31.44%-58.75%). At the time of imatinib discontinuation, non-relapsing patients had significantly higher numbers of natural killer cells of the cytotoxic CD56dim subset than had relapsing patients, while CD56bright natural killer cells, T cells and their subsets did not differ significantly. Furthermore, the CD56dim natural killer-cell count was an independent prognostic factor of molecular-relapse free survival in a multivariate analysis. However, expression of natural killer-cell activating receptors, BCR-ABL1+ leukemia cell line K562-specific degranulation and cytokine-induced interferon-gamma secretion were decreased in non-relapsing and relapsing patients as compared with healthy individuals. After imatinib cessation, the natural killer-cell count increased significantly and stayed higher in non-relapsing patients than in relapsing patients, while receptor expression and functional properties remained unchanged. Altogether, our results suggest that natural killer cells may play a role in controlling leukemia-initiating cells at the origin of relapse after imatinib cessation, provided that these cells are numerous enough to compensate for their functional defects. Further research will decipher mechanisms underlying functional differences between natural killer cells from patients and healthy individuals and evaluate the potential interest of immunostimulatory approaches in tyrosine kinase inhibitor discontinuation strategies. (ClinicalTrial.gov Identifier NCT00478985).