RESUMEN
BACKGROUND: Induction with daratumumab-based regimens followed by autologous stem cell transplantation is the current standard for newly diagnosed multiple myeloma (NDMM) patients eligible for intensive chemotherapy. However, concerns emerged regarding potential negative effects following daratumumab-based treatment on CD34+ mobilization. We here compared CD34+ mobilization and clonogenic potential between daratumumab and non-daratumumab based therapy without upfront plerixafor administration among patients affected by NDMM. MATERIALS AND METHODS: Clinical, mobilization and clonogenic data from 41 consecutively enrolled NDMM patients were analyzed. Patients underwent collection of autologous CD34+ by apheresis at the ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy, from January 2021 to March 2023. Clonogenicity analysis was performed on BFU-E and CFU-GM. RESULTS: Seventy-five percent of daratumumab-treated patients underwent >1 apheresis, compared to 24% of non-daratumumab patients (p=0.0017). Daratumumab-treated patients had significantly lower CD34+ count (mean 38 vs 79/µL, respectively; p=0.0011), with a median CD34+ harvest of 3.98×106/kg (range 1.68-9.18) vs 6.87×106/kg (range 1.63-16.85) in non-daratumumab-treated (p=0.0006). In multivariate analysis the likelihood of undergoing >1 apheresis was significantly higher in older patients (OR 1.2, 95% CI 1-1.4, Z=2.10, p=0.03) and daratumumab-treated patients (OR 15, 95% CI 2.8-129, p=0.004). Moreover, daratumumab-based induction therapy demonstrated an independent negative association with BFU-E colony formation (p=0.0148), even when accounting for patient age and CD34+ levels. DISCUSSION: Our findings underscore the impact of daratumumab-based treatment on CD34+ mobilization in a real-life, upfront plerixafor-free population of NDMM patients. Higher probability of requiring multiple apheresis occurred among daratumumab-treated patients. Interestingly, the observation that daratumumab might negatively impact BFU-E colony formation, independent of CD34+ cell count, offers novel biological perspectives. Appropriate strategies should be adopted by the Apheresis teams to mitigate these potential negative effects.
Asunto(s)
ADP-Ribosil Ciclasa 1 , Anticuerpos Monoclonales , Antígenos CD34 , Movilización de Célula Madre Hematopoyética , Mieloma Múltiple , Humanos , Mieloma Múltiple/terapia , Mieloma Múltiple/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Movilización de Célula Madre Hematopoyética/métodos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/farmacología , Adulto , Glicoproteínas de MembranaRESUMEN
Ruxolitinib (RUX) is extensively used in myelofibrosis (MF). Despite its early efficacy, most patients lose response over time and, after discontinuation, have a worse overall survival (OS). Currently, response criteria able to predict OS in RUX-treated patients are lacking, leading to uncertainty regarding the switch to second-line treatments. In this study, we investigated predictors of survival collected after 6 months of RUX in 209 MF patients participating in the real-world ambispective observational RUXOREL-MF study (NCT03959371). Multivariable analysis identified the following risk factors: (1) RUX dose <20 mg twice daily at baseline, months 3 and 6 (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.07-3.00; P = .03), (2) palpable spleen length reduction from baseline ≤30% at months 3 and 6 (HR, 2.26; 95% CI, 1.40-3.65; P = .0009), (3) red blood cell (RBC) transfusion need at months 3 and/or 6 (HR, 1.66; 95% CI, 0.95-2.88; P = .07), and (4) RBC transfusion need at all time points (ie, baseline and months 3 and 6; HR, 2.32; 95% CI, 1.19-4.54; P = .02). Hence, we developed a prognostic model, named Response to Ruxolitinib After 6 Months (RR6), dissecting 3 risk categories: low (median OS, not reached), intermediate (median OS, 61 months; 95% CI, 43-80), and high (median OS, 33 months; 95% CI, 21-50). The RR6 model was validated and confirmed in an external cohort comprised of 40 MF patients. In conclusion, the RR6 prognostic model allows for the early identification of RUX-treated MF patients with impaired survival who might benefit from a prompt treatment shift.
Asunto(s)
Mielofibrosis Primaria , Humanos , Nitrilos , Mielofibrosis Primaria/inducido químicamente , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/tratamiento farmacológico , Pronóstico , Pirazoles/efectos adversos , Pirimidinas , Estudios RetrospectivosRESUMEN
Chronic Myeloid Leukemia is a clonal disorder characterized by the presence of the Ph-chromosome and the BCR-ABL tyrosine-kinase (TK). Target-therapy with Imatinib has greatly improved its outcome. Deeper and faster responses are reported with the second-generation TKI Nilotinib. Sustained responses may enable TKI discontinuation. However, even in a complete molecular response, some patients experience disease recurrence possibly due to persistence of quiescent leukemic CD34+/lin-Ph+ stem cells (LSCs). Degree and mechanisms of LSCs clearance during TKI treatment are not clearly established. The PhilosoPhi34 study was designed to verify the in-vivo activity and timecourse of first-line Nilotinib therapy on BM CD34+/lin-Ph+ cells clearance. Eighty-seven CP-CML patients were enrolled. BM cells were collected and tested for Ph+ residual cells, at diagnosis, 3, 6 and 12 months of treatment. FISH analysis of unstimulated CD34+/lin- cells in CCyR patients were positive in 8/65 (12.3%), 5/71 (7%), 0/69 (0%) evaluable tests, respectively. Per-Protocol analysis response rates were as follows: CCyR 95% at 12 months, MR4.5 31% and 46% at 12 and 36 months, respectively. An exploratory Gene Expression Profiling (GEP) study of CD34+/lin- cells was performed on 30 patients at diagnosis and after, on 79 patients at diagnosis vs 12 months of nilotinib treatment vs 10 healthy subjects. Data demonstrated some genes significantly different expressed: NFKBIA, many cell cycle genes, ABC transporters, JAK-STAT signaling pathway (JAK2). In addition, a correlation between different expression of some genes (JAK2, OLFM4, ICAM1, NFKBIA) among patients at diagnosis and their achievement of an early and deeper MR was observed.
Asunto(s)
Antineoplásicos/uso terapéutico , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores Farmacológicos , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Médula Ósea/patología , Estudios de Casos y Controles , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Femenino , Perfilación de la Expresión Génica , Factor Estimulante de Colonias de Granulocitos/genética , Factor Estimulante de Colonias de Granulocitos/metabolismo , Humanos , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Inhibidor NF-kappaB alfa/genética , Inhibidor NF-kappaB alfa/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Cromosoma Filadelfia , Estudios Prospectivos , RecurrenciaAsunto(s)
Inhibidores de las Cinasas Janus/efectos adversos , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/etiología , Mielofibrosis Primaria/complicaciones , Pirazoles/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Duración de la Terapia , Femenino , Humanos , Italia/epidemiología , Inhibidores de las Cinasas Janus/uso terapéutico , Masculino , Persona de Mediana Edad , Mutación , Tasa de Mutación , Neoplasias Primarias Secundarias/epidemiología , Nitrilos , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/epidemiología , Mielofibrosis Primaria/etiología , Pirazoles/uso terapéutico , Pirimidinas , Adulto JovenRESUMEN
Chronic myeloid leukemia (CML) is characterized by the constitutive tyrosine kinase activity of the oncoprotein BCR-ABL1 in myeloid progenitor cells that activates multiple signal transduction pathways leading to the leukemic phenotype. The tyrosine-kinase inhibitor (TKI) nilotinib inhibits the tyrosine kinase activity of BCR-ABL1 in CML patients. Despite the success of nilotinib treatment in patients with chronic-phase (CP) CML, a population of Philadelphia-positive (Ph+) quiescent stem cells escapes the drug activity and can lead to drug resistance. The molecular mechanism by which these quiescent cells remain insensitive is poorly understood. The aim of this study was to compare the gene expression profiling (GEP) of bone marrow (BM) CD34+/lin- cells from CP-CML patients at diagnosis and after 12 months of nilotinib treatment by microarray, in order to identify gene expression changes and the dysregulation of pathways due to nilotinib action. We selected BM CD34+/lin- cells from 78 CP-CML patients at diagnosis and after 12 months of first-line nilotinib therapy and microarray analysis was performed. GEP bioinformatic analyses identified 2,959 differently expressed probes and functional clustering determined some significantly enriched pathways between diagnosis and 12 months of nilotinib treatment. Among these pathways, we observed the under expression of 26 genes encoding proteins belonging to the cell cycle after 12 months of nilotinib treatment which led to the up-regulation of chromosome replication, cell proliferation, DNA replication, and DNA damage checkpoint at diagnosis. We demonstrated the under expression of the ATP-binding cassette (ABC) transporters ABCC4, ABCC5, and ABCD3 encoding proteins which pumped drugs out of the cells after 12 months of nilotinib. Moreover, GEP data demonstrated the deregulation of genes involved in the JAK-STAT signaling pathway. The down-regulation of JAK2, IL7, STAM, PIK3CA, PTPN11, RAF1, and SOS1 key genes after 12 months of nilotinib could demonstrate the up-regulation of cell cycle, proliferation and differentiation via MAPK and PI3K-AKT signaling pathways at diagnosis.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/sangre , Ciclo Celular/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Quinasas Janus/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Proteínas de Neoplasias/sangre , Pirimidinas/administración & dosificación , Factores de Transcripción STAT/sangre , Transducción de Señal/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoAsunto(s)
Células de la Médula Ósea/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Pirimidinas/farmacología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD34/análisis , Células de la Médula Ósea/patología , Recuento de Células , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Células Madre Neoplásicas/patología , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder with heterogeneous biological and clinical features. The biomolecular mechanisms of CML response to tyrosine-kinase inhibitors are not fully defined. OBJECTIVE: We undertook a gene expression profiling (GEP) study of selected bone marrow (BM) CD34+/lin- cells of chronic-phase CML patients at diagnosis and after 12 months of TKI nilotinib to investigate molecular signatures characterizing both conditions.
Asunto(s)
Células de la Médula Ósea/metabolismo , Perfilación de la Expresión Génica/métodos , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/genética , Pirimidinas/uso terapéutico , Antígenos CD34/sangre , Células de la Médula Ósea/patología , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia Mieloide de Fase Crónica/sangre , Recuento de Leucocitos , Proteínas Tirosina Quinasas/uso terapéutico , Factores de Tiempo , Resultado del TratamientoRESUMEN
A 43 year-old woman presented with fever, abdominal pain, epato-splenomegaly, ascites, cholestasis, anemia, thrombocytopenia and previous diagnosis of sclerosing cholangitis based on liver biopsy and endoscopic retrograde cholangiopancreatography(ERCP). The bone marrow biopsy and the revision of liver biopsy using antitryptase stain diagnosed systemic mastocytosis. Because of the aggressive course of the disease the patient was treated with an acute myeloid leukaemia chemotherapy regimen without success.
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Colangitis Esclerosante/diagnóstico , Mastocitosis Sistémica/diagnóstico , Dolor Abdominal/etiología , Corticoesteroides/uso terapéutico , Adulto , Sustitución de Aminoácidos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia con Aguja , Médula Ósea/patología , Síndrome de Budd-Chiari/etiología , Colangiopancreatografia Retrógrada Endoscópica , Células Clonales/patología , Citarabina/administración & dosificación , Diagnóstico Diferencial , Diarrea/etiología , Resultado Fatal , Femenino , Rubor/etiología , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Humanos , Idarrubicina/administración & dosificación , Hígado/patología , Linfoma/diagnóstico , Mastocitos/patología , Mastocitosis Sistémica/complicaciones , Mastocitosis Sistémica/tratamiento farmacológico , Mastocitosis Sistémica/genética , Mastocitosis Sistémica/patología , Mutación Missense , Mutación Puntual , Prednisona/administración & dosificación , Proteínas Proto-Oncogénicas c-kit/genética , RecurrenciaRESUMEN
BACKGROUND AND OBJECTIVES: The incidence of invasive filamentous fungal infections in hematologic patients is increasing as a consequence of high dose chemotherapy and bone marrow transplant procedures. Mortality is usually very high. The diagnosis is often difficult and yet a fast, accurate diagnosis is of fundamental importance for treating the infection and planning subsequent management of the hematologic disease. We evaluated the sensitivity of computed tomography (CT)-guided percutaneous biopsy in diagnosing pulmonary fungal infections. DESIGN AND METHODS: Between 1997 and 2002 we performed 17 CT-guided percutaneous transthoracic lung biopsies in 17 hematologic patients with suspected filamentous fungi infection with negative BAL, to obtain a certain diagnosis and to know what species of fungi was responsible for infection. In all cases suspected mycosis began during the post-chemotherapy aplastic period. Patients were receiving antifungal therapy at the time of all biopsies. When the platelet count rose above 50 x 10(9)/L, CT-guided percutaneous lung biopsy with fine-needle aspiration for cytology was performed. RESULTS: Twelve of 17 patients had histologic confirmation of the fungal infection (70.5%), 8 with Aspergillus spp. 4 with Mucorales spp. Biopsies provided non-specific results in 4 cases; in 2 of these cases, clinical course and response to therapy confirmed the diagnosis of mycosis; in the last case bronchoalveolar carcinoma was found as a new diagnosis. Cultures were positive in only 6 cases, all for Aspergillus spp. The sensitivity of CT-guided percutaneous lung biopsy was 70.6% and its positive predictive value (PPV) was 100%. This procedure provided an immediate diagnosis and only one side-effect (1 pneumothorax, without complications). INTERPRETATION AND CONCLUSIONS: Histologic discrimination between aspergillosis and mucormycosis is very important for deciding secondary prophylaxis during transplant procedures, because Mucor is usually resistant to azoles.