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1.
Cancer Chemother Pharmacol ; 88(5): 887-897, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34370076

RESUMEN

PURPOSE: This study aimed at evaluating the effect of rucaparib on the pharmacokinetics of rosuvastatin and oral contraceptives in patients with advanced solid tumors and the safety of rucaparib with and without coadministration of rosuvastatin or oral contraceptives. METHODS: Patients received single doses of oral rosuvastatin 20 mg (Arm A) or oral contraceptives ethinylestradiol 30 µg + levonorgestrel 150 µg (Arm B) on days 1 and 19 and continuous doses of rucaparib 600 mg BID from day 5 to 23. Serial blood samples were collected with and without rucaparib for pharmacokinetic analysis. RESULTS: Thirty-six patients (n = 18 each arm) were enrolled and received at least 1 dose of study drug. In the drug-drug interaction analysis (n = 15 each arm), the geometric mean ratio (GMR) of maximum concentration (Cmax) with and without rucaparib was 1.29 for rosuvastatin, 1.09 for ethinylestradiol, and 1.19 for levonorgestrel. GMR of area under the concentration-time curve from time zero to last quantifiable measurement (AUC0-last) was 1.34 for rosuvastatin, 1.43 for ethinylestradiol, and 1.56 for levonorgestrel. There was no increase in frequency of treatment-emergent adverse events (TEAEs) when rucaparib was given with either of the probe drugs. In both arms, most TEAEs were mild in severity and considered unrelated to study treatment. CONCLUSION: Rucaparib 600 mg BID weakly increased the plasma exposure to rosuvastatin or oral contraceptives. Rucaparib safety profile when coadministered with rosuvastatin or oral contraceptives was consistent with that of rucaparib monotherapy. Dose adjustments of rosuvastatin and oral contraceptives are not necessary when coadministered with rucaparib. ClinicalTrials.gov NCT03954366; Date of registration May 17, 2019.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Anticonceptivos Orales/farmacocinética , Neoplasias/tratamiento farmacológico , Rosuvastatina Cálcica/farmacocinética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anticonceptivos Orales/administración & dosificación , Interacciones Farmacológicas , Etinilestradiol/farmacocinética , Femenino , Humanos , Indoles/administración & dosificación , Levonorgestrel/farmacocinética , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Rosuvastatina Cálcica/administración & dosificación
2.
Hematology ; 26(1): 556-564, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34384334

RESUMEN

BACKGROUND: Azacitidine (AZA) is the standard of care for higher-risk myelodysplastic syndrome (HR-MDS) patients ineligible for intensive therapy. Clinical outcome discrepancies reported in clinical trials and real-life settings stimulate the search for new prognostic factors. METHODS: We retrospectively evaluated 315 MDS, 20-30% blast acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML) patients treated with azacitidine in 12 centers cooperating within the Polish Adult Leukemia Group (PALG). RESULTS: The median number of AZA cycles was 7 (1-69) and 24% patients received fewer than 4 cycles (early failure, EF). Serum albumin level was an independent predictor of EF occurrence. Complete remission (CR) was obtained in 20% and partial remission (PR) in 12% of patients. Hematologic improvement - erythroid (HI-E), neutrophil (HI-N), or platelet (HI-P) was achieved in 51%, 36%, and 48% of patients, respectively. No factors significantly predicted CR or PR in the multivariate analysis. For HI-E and HI-P, lower LDH level predicted response. Median survival was 15 (13-19) months. Lower serum albumin level, serious infection and receiving <4 AZA cycles independently predicted a worse overall survival (OS) (p < 0.05). CONCLUSION: Serum albumin assessment before azacitidine treatment can help to identify patients with higher risk of early failure and worse clinical outcome.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Albúmina Sérica Humana/análisis , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento
3.
Cancer Chemother Pharmacol ; 88(2): 259-270, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33909097

RESUMEN

PURPOSE: The poly(ADP-ribose) polymerase inhibitor rucaparib is approved for the treatment of patients with recurrent ovarian and metastatic castration-resistant prostate cancer; however, limited data are available on its use in patients with hepatic dysfunction. This study investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of rucaparib in patients with advanced solid tumors. METHODS: Patients with normal hepatic function or moderate hepatic impairment according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria were enrolled and received a single oral dose of rucaparib 600 mg. Concentrations of rucaparib and its metabolite M324 in plasma and urine were measured. Pharmacokinetic parameters were compared between hepatic function groups, and safety and tolerability were assessed. RESULTS: Sixteen patients were enrolled (n = 8 per group). Rucaparib maximum concentration (Cmax) was similar, while the area under the concentration-time curve from time 0 to infinity (AUC0-inf) was mildly higher in the moderate hepatic impairment group than in the normal control group (geometric mean ratio, 1.446 [90% CI 0.668-3.131]); similar trends were observed for M324. Eight (50%) patients experienced ≥ 1 treatment-emergent adverse event (TEAE); 2 had normal hepatic function and 6 had moderate hepatic impairment. CONCLUSION: Patients with moderate hepatic impairment showed mildly increased AUC0-inf for rucaparib compared to patients with normal hepatic function. Although more patients with moderate hepatic impairment experienced TEAEs, only 2 TEAEs were considered treatment related. These results suggest no starting dose adjustment is necessary for patients with moderate hepatic impairment; however, close safety monitoring is warranted.


Asunto(s)
Indoles/farmacocinética , Indoles/uso terapéutico , Hepatopatías/etiología , Neoplasias/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Adulto , Anciano , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Área Bajo la Curva , Femenino , Humanos , Hígado/efectos de los fármacos , Pruebas de Función Hepática/métodos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo
5.
Front Oncol ; 9: 1477, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-32010610

RESUMEN

The aim of the following case report is to provide a description of acute lymphoblastic leukemia (ALL) in a patient with Netherton syndrome (NS). A 15-year-old male with NS was referred with suspicion of acute leukemia. Severe anemia, leukocytosis, thrombocytopenia, and elevated CRP level were demonstrated in pre-hospital laboratory tests. Physical examination revealed generalized ichthyosiform erythroderma. ALL was diagnosed on the basis of bone marrow biopsy. The patient was initially classified as CNS3 status. No signals indicating fusion of BCR/ABL1, ETV6, and RUNX1 genes and MLL gene rearrangement were found in the cytogenetic analysis. The patient was qualified for chemotherapy and treated according to ALL IC-BFM 2009 protocol for high-risk ALL. During induction therapy, severe skin toxicity occurred (WHO grade III), which prompted the modification of treatment down to intermediate-risk strategy. In the course of reinduction therapy, severe chemotherapy-induced adverse drug reactions occurred, including progression of skin toxicity to WHO grade IV. The patient achieved complete remission. In view of life-threatening toxicities and the confirmed complete remission, intensive chemotherapy regimen was discontinued and maintenance treatment was started. Because of the baseline CNS3 status, the patient received cranial radiotherapy. Whole exome sequencing (WES) was used to identify disease-associated mutations. WES revealed two germline mutations: a novel premature termination variant in SPINK5 (p.Cys510*), along with a novel potentially pathogenic variant in NUP214 (p.Arg815Gln). Somatic mutations were known pathogenic variants of JAK2 (p.Arg683Gly), IL17RC (p.Ala303Thr), and potentially pathogenic non-synonymous variants of TTN (p.Gly1091Arg and p.Pro17245Leu), ACTN2 (p.Ile143Leu), TRPV3 (p.Arg729*), and COL7A1 (p.Glu2842fs) genes. Currently, the patient continues maintenance chemotherapy, with stable status of skin lesions and no features of ALL relapse. To our knowledge, this is the first report of ALL in a patient with NS. As has been presented, in such patients, optimal treatment according to the current protocols is extremely difficult. WES was used to confirm the diagnosis of Ph-like ALL in our patient. The detection of JAK2 gene mutation offers the possibility of therapy personalization. A specific signature of rare germline variants and somatic mutations can be proposed as a factor predisposing to the co-incidence of ALL and NS.

6.
Contemp Oncol (Pozn) ; 19(1): 43-7, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26199570

RESUMEN

AIM OF THE STUDY: To evaluate the efficacy and safety of Yttrium-90 Ibritumomab Tiuxetan ((90)Y-IT) as a consolidation therapy in the management of DLBCL. MATERIAL AND METHODS: Patients with primary refractory or high-risk DLBCL (n = 18), ineligible for autologous stem-cell transplantation, were included in a retrospective study performed at three centers by the Polish Lymphoma Research Group (PLRG). All patients (mean age 61, range 35-82) either didn't achieve a complete response or didn't complete the scheduled therapy due to its complications. Response rates (CR, PR, SD, PD) according to Cheson criteria, overall survival (OS), progression-free survival (PFS) and adverse effects of radioimmunotherapy were analyzed. RESULTS: Consolidation radioimmunotherapy increased the CR rate from 38% (n = 7) to 82% (n = 15). One patient remained in PR, one patient remained in SD, while one patient remained in PD. During a median follow-up of five years, 11 patients (62%) were alive with no recurrence, 4 patients (22%) were alive with relapse while 3 patients (16%) died. There was no statistically significant difference in PFS between those in CR and those in PR before (90)Y-IT. CONCLUSIONS: Radioimmunotherapy is an effective consolidation therapy for high risk/refractory DLBCL patients and worthy of further investigation in prospective trials.

7.
J Clin Immunol ; 27(3): 339-46, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17345151

RESUMEN

PURPOSE: The purpose of this study was to assess humoral response to influenza vaccine in patients (pts) with non-Hodgkin lymphoma (NHL) as compared to healthy subjects (ctrl). PATIENTS AND METHODS: In two epidemic seasons, 2003/2004 and 2004/2005, 163 pts and 92 ctrl were vaccinated. Antibody titers to hemagglutinin (HA) and neuraminidase (NA) were measured in serum samples collected before vaccination, and 1 and 6 months apart. Changes in antibody titers were assessed by comparing geometric mean titers (GMT), mean fold increases (MFI), and seroprotection and seroresponse rates to baseline values. RESULTS: Pts vaccinated in 2003/2004 had, after 1 month, increase in GMT by a factor of 8.64-26.60 for antihemagglutinin antibodies (HI) and 6.93-12.66 for antineuraminidase antibodies (NI), as compared to factor of 9.12-24.41 for HI and 4.83-10.31 for NI in ctrl. At 1 month after vaccination, seroprotection and seroresponse rates were similar in both groups, ranging from 68.42 to 84.21% and 71.93 to 94.74% in NHL, and 66.67-82.22% and 62.22-86.67% in ctrl, respectively. Pts vaccinated in 2004/2005 had increase in the GMT by a factor of 38.76-41.49 for HI and 26.59-30.31 for NI, as compared to factor of 81.19-104.32 for HI and 52.16-54.52 for NI in ctrl. Seroprotection and seroresponse rates were lower in the former group, ranging from 62.11 to 65.26% and 74.47 to 77.66%, respectively. In both seasons, pts achieved titres of antibodies greater than the protective threshold, irrespective of the previous chemotherapy administration. CONCLUSIONS: The results indicate that influenza vaccination induces sufficient immune response in pts with NHL, irrespective of previous chemotherapy.


Asunto(s)
Vacunas contra la Influenza/inmunología , Linfoma no Hodgkin/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos/sangre , Anticuerpos/inmunología , Femenino , Hemaglutininas/inmunología , Humanos , Virus de la Influenza A/inmunología , Gripe Humana/inmunología , Gripe Humana/prevención & control , Linfoma no Hodgkin/sangre , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Neuraminidasa/inmunología , Neuraminidasa/metabolismo , Factores de Tiempo
8.
Pol J Pathol ; 57(2): 63-70, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-17019967

RESUMEN

During the course of lymphoma, a clinically more aggressive process with different morphology may develop, referred to as lymphoma transformation. Clonal relationship and pathogenic mechanism of this process are widely debated. The aim of the study was to evaluate morphology, immunophenotype (including EBV status) and clonal relationship in nine cases of lymphoma transformation. Among the six patients with low grade B-cell lymphomas three transformed into high grade B-cell lymphomas (two into diffuse large B-cell lymphoma, one into Burkitt lymphoma) and three into Hodgkin lymphoma. Three other patients with Hodgkin lymphoma presented with transformation into diffuse large B-cell lymphoma in two patients and peripheral T-cell lymphoma in one patient. In all cases there was a sudden clinical change as well as change in morphology and phenotype. In five of the nine patients studied EBV-LMP1 was demonstrated by immunohistochemistry in large transformed lymphoma cells. In two cases molecular studies revealed a different pattern of immunoglobulin gene rearrangement in the large transformed cells as compared to the small cells of primary indolent lymphoma. Thus, they represented secondary, arising de novo neoplasm.


Asunto(s)
Transformación Celular Neoplásica/patología , Reordenamiento Génico de Linfocito B/genética , Inmunofenotipificación , Linfoma/patología , Adulto , Anciano , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/inmunología , Progresión de la Enfermedad , Femenino , Humanos , Linfoma/genética , Masculino , Persona de Mediana Edad
9.
Vaccine ; 24(44-46): 6620-3, 2006 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-16870313

RESUMEN

Lymphoma disease and immunosuppressive drugs used in this case cause immunity disorders increasing the risk of severe infections, including influenza. There are opinions that patients from high-risk group are not able to respond to vaccination effectively and vaccination may contribute to exacerbation of the chronic disease. The aim was to assess humoral response to influenza vaccine in 32 patients with non-Hodgkin malignant lymphoma (mean age 57.2) and 32 healthy subjects (mean age 44.3). Sixteen patients were treated with immunosupressive drugs (group A) and 11 were not subjected to this therapy (group B). Levels of antihemagglutinin (anti-HA) antibodies were assessed in sera before vaccination and after 1 month by hemagglutination inhibition test. Nasal and throat swabs were collected from persons with influenza symptoms during the study to detect the etiological agent of the infection. Post-vaccination anti-HA antibody levels were significantly higher than pre-vaccination values and mean fold increases (MFI) ranged from 9.3 to 12.2 in patients and from 27.6 to 44.3 in healthy subjects. The percentage of patients with the protective anti-HA antibody titers > or =1:40 (protection rate) ranged after vaccination from 59.4% to 68.8%. The percentage of patients with at least a four-fold increase of anti-HA antibody titers (response rate) after vaccination ranged from 46.9% to 68.8%. There were no significant differences in antibody levels between patients treated with immunosuppressive drugs and those not treated. No respiratory infections were laboratory confirmed. This study showed that influenza vaccine is less immunogenic in patients with non-Hodgkin malignant lymphoma, because it induces antibody production in lower titers in comparison to the production in healthy people. Despite this, influenza vaccine should be offered to this group, considering high MFI values and response rates as well as the protective effect for individual patients.


Asunto(s)
Anticuerpos Antivirales/biosíntesis , Formación de Anticuerpos/inmunología , Vacunas contra la Influenza/inmunología , Linfoma de Células B/inmunología , Linfoma no Hodgkin/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Glicoproteínas Hemaglutininas del Virus de la Influenza , Humanos , Inmunidad Activa/efectos de los fármacos , Inmunidad Activa/inmunología , Vacunas contra la Influenza/uso terapéutico , Gripe Humana/inmunología , Gripe Humana/prevención & control , Masculino , Persona de Mediana Edad , Vacunación
10.
Arch Immunol Ther Exp (Warsz) ; 53(5): 454-64, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16314829

RESUMEN

INTRODUCTION: Recent studies suggest that multiple myeloma (MM) triggers osteoclastogenesis by disrupting the balance between the receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG), its natural antagonist. MATERIAL/METHODS: Determinations of bone marrow (BM) and serum OPG and sRANKL concentrations were performed in 133 MM patients and 42 healthy subjects by the ELISA method using Osteoprotegerin ELISA and sRANKL ELISA kits. RESULTS: MM patients had elevated serum levels of OPG compared with controls (p<0.0001) and OPG levels were higher in patients with renal failure and patients with hipercalcemia (p<0.001 and p=0.04, respectively). Serum OPG levels correlated with age, serum beta 2-microglobulin, and BM OPG concentrations and did not correlate with the presence of osteolysis or with stage of disease. sRANKL serum levels in MM patients and in controls were not statistically different (p=0.42). In MM patients, serum OPG and sRANKL levels were similar at diagnosis and in the plateau phase of disease. There was a correlation between BM and serum sRANKL concentrations (p<0.001). Median values of the sRANKL/OPG ratio for BM and serum of MM patients were 0.14 and 0.11, respectively. The median value of the sRANKL/OPG ratio for the serum of controls was 0.11. CONCLUSIONS: In 20% of MM patients, serum OPG levels are elevated, and this may be a compensative reaction related to increased bone destruction. There is not statistically significant relationship between sRANKL serum and BM levels and the main clinical and laboratory parameters of the disease. Determination of BM and the serum sRANKL/OPG ratio seems to have no clinical value.


Asunto(s)
Médula Ósea/química , Proteínas Portadoras/sangre , Glicoproteínas/sangre , Glicoproteínas de Membrana/sangre , Mieloma Múltiple/metabolismo , Receptores Citoplasmáticos y Nucleares/sangre , Receptores del Factor de Necrosis Tumoral/sangre , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Portadoras/análisis , Ensayo de Inmunoadsorción Enzimática , Femenino , Glicoproteínas/análisis , Humanos , Masculino , Glicoproteínas de Membrana/análisis , Persona de Mediana Edad , Osteoprotegerina , Ligando RANK , Receptor Activador del Factor Nuclear kappa-B , Receptores Citoplasmáticos y Nucleares/análisis , Receptores del Factor de Necrosis Tumoral/análisis
11.
Leuk Lymphoma ; 46(3): 471-5, 2005 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15621842

RESUMEN

We describe the case of a 47-year-old man admitted to the Department of Hematology because of fever, enlarged cervical and supraclavicular lymph nodes, hepatosplenomegaly and non-specific lung infiltrations. The histopathological examination of the cervical lymph node revealed Hodgkin's lymphoma (HL) NS type I. Clinical evaluation revealed stage IVB according to Ann Arbor classification and the presence of 5 unfavorable prognostic factors according to the International Prognostic Index. Despite BEACOPP chemotherapy (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), the enlarged lymph nodes, lung infiltrations and fever persisted. Microbiological and serological tests did not lead to the identification of any viral or bacterial pathogens. Bronchoscopy showed chronic inflammation and post-tuberculosis (TB) scars in bronchi without acid-fast bacilli in bronchoalveolar lavage (BAL) in culture and polymerase chain reaction (PCR) tests. However, the biopsy of the supraclavicular lymph node revealed multiple, caseating and necrotizing granulomatous lesions with scattered Reed-Sternberg (R-S) cells. The auramin staining presented acid-fast bacilli and allowed the diagnosis of productive and caseating TB coexisting with HL. The 4 tuberculostatics regimen and ABVD chemotherapy (adriamycin, bleomycin, vincristine, dacarbazine) resulted in a complete clinical response after 3 months of treatment. In conclusion, the association between HL and TB must be considered, especially in countries where the latter is endemic. The diagnosis may be difficult due to similarities in the clinical course, laboratory tests and imaging procedures.


Asunto(s)
Enfermedad de Hodgkin/complicaciones , Ganglios Linfáticos/patología , Tuberculosis Ganglionar/complicaciones , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antituberculosos/uso terapéutico , Enfermedad de Hodgkin/patología , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Tuberculosis Ganglionar/patología
12.
Med Sci Monit ; 10(9): PI93-5, 2004 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-15328493

RESUMEN

BACKGROUND: Metamizole is a common analgesic and antipyretic drug. However, its use has been associated with a risk of side-effects involving agranulocytosis and aplastic anemia. These reactions are rare and unpredictable. The aim of this prospective study was to evaluate the risks of these complications in Poland, where this medication is available without prescription. MATERIAL/METHODS: Six hematological centers, serving approximately 40% (ca. 15 million people) of the country's population, participated in the study. All cases of agranulocytosis and aplastic anemia were recorded and their severity and association with the use of drugs, especially metamizole sodium, were evaluated. All the patients receiving cytostatic or immunosuppressive drugs were excluded. RESULTS: During the 12 months of the study, 2 cases of aplastic anemia and no cases of agranulocytosis were confirmed which may have been associated with the use of metamizole. Overall, we recorded 16 cases of agranulocytosis and 27 cases of aplastic anemia. The two cases of metamizole sodium-induced aplastic anemia were non-fatal in character. CONCLUSIONS: Considering the consumption of 112,300,094 tablets of metamizole in Poland a year, the figures obtained result in an incidence of 0.25 cases of aplastic anemia per 1 million persons per day of treatment; this value being less than that for other nonsteroidal anti-inflammatory drugs. Nevertheless, caution is recommended in the application of metamizole, particularly over long periods and in large doses.


Asunto(s)
Agranulocitosis , Anemia Aplásica , Antiinflamatorios no Esteroideos/efectos adversos , Dipirona/efectos adversos , Administración Oral , Agranulocitosis/epidemiología , Agranulocitosis/etiología , Anemia Aplásica/epidemiología , Anemia Aplásica/etiología , Humanos , Medicamentos sin Prescripción/efectos adversos , Polonia , Estudios Prospectivos
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