RESUMO
BACKGROUND: Belantamab mafodotin had single-agent activity in patients with relapsed or refractory multiple myeloma, a finding that supports further evaluation of the agent in combination with standard-care therapies. METHODS: In this phase 3, open-label, randomized trial, we evaluated belantamab mafodotin, bortezomib, and dexamethasone (BVd), as compared with daratumumab, bortezomib, and dexamethasone (DVd), in patients who had progression of multiple myeloma after at least one line of therapy. The primary end point was progression-free survival. Key secondary end points were overall survival, response duration, and minimal residual disease (MRD)-negative status. RESULTS: In total, 494 patients were randomly assigned to receive BVd (243 patients) or DVd (251 patients). At a median follow-up of 28.2 months (range, 0.1 to 40.0), median progression-free survival was 36.6 months (95% confidence interval [CI], 28.4 to not reached) in the BVd group and 13.4 months (95% CI, 11.1 to 17.5) in the DVd group (hazard ratio for disease progression or death, 0.41; 95% CI, 0.31 to 0.53; P<0.001). Overall survival at 18 months was 84% in the BVd group and 73% in the DVd group. An analysis of the restricted mean response duration favored BVd over DVd (P<0.001). A complete response or better plus MRD-negative status occurred in 25% of the patients in the BVd group and 10% of those in the DVd group. Grade 3 or higher adverse events occurred in 95% of the patients in the BVd group and 78% of those in the DVd group. Ocular events were more common in the BVd group than in the DVd group (79% vs. 29%); such events were managed with dose modifications, and events of worsening visual acuity mostly resolved. CONCLUSIONS: As compared with DVd therapy, BVd therapy conferred a significant benefit with respect to progression-free survival among patients who had relapsed or refractory multiple myeloma after at least one line of therapy. Most patients had grade 3 or higher adverse events. (Funded by GSK; DREAMM-7 ClinicalTrials.gov number, NCT04246047; EudraCT number, 2018-003993-29.).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Dexametasona , Mieloma Múltiplo , Intervalo Livre de Progressão , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Bortezomib/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/uso terapêutico , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Dexametasona/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Neoplasia Residual , Estimativa de Kaplan-Meier , Análise de SobrevidaRESUMO
In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved to have a superior clinical benefit over pomalidomide and dexamethasone with a manageable toxicity profile, leading to its approval for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. We report here a real-world experience of 200 cases of RRMM treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was two, with 51% of cases undergoing autologous stem cell transplant and 73% having been exposed to daratumumab. After a median follow-up of 9 months, 126 patients had stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate was 55.4%, a finding in line with the pivotal trial results. Regarding adverse events, the toxicity profile in our cohort was similar to that in the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival was 7 months, which was shorter than that observed in ELOQUENT-3, probably because of the different clinical characteristics of the two cohorts. Interestingly, International Staging System stage III disease was associated with worse progression-free survival (hazard ratio=2.55). Finally, the median overall survival of our series was shorter than that observed in the ELOQUENT-3 trial (17.5 vs. 29.8 months). In conclusion, our real-world study confirms that EloPd is a safe and possible therapeutic choice for patients with RRMM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.
Assuntos
Mieloma Múltiplo , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/uso terapêutico , Lenalidomida/uso terapêutico , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/etiologia , Inibidores de Proteassoma/uso terapêutico , Estudos Retrospectivos , Ensaios Clínicos Controlados como AssuntoRESUMO
The ELOQUENT-3 trial demonstrated the superiority of the combination of elotuzumab, pomalidomide, and dexamethasone (EloPd) in terms of efficacy and safety, compared to Pd in relapsed/refractory multiple myeloma (RRMM), who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor. The present study is an 18-month follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloPd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 17.7 months, 213 patients (66.4%) experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 7.5 and 19.2 months, respectively. The updated multivariate analysis showed a significant reduction of PFS benefit magnitude both in advanced International Staging System (ISS) (II and III) stages and previous exposure to daratumumab cases. Instead, advanced ISS (II and III) stages and more than 2 previous lines of therapy maintained an independent prognostic impact on OS. Major adverse events included grade three-fourths neutropenia (24.9%), anemia (13.4%), lymphocytopenia (15.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 19.3% and 8.7%, respectively. A slight increase in the incidence of neutropenia and lymphocytopenia was registered with longer follow-up. In conclusion, our real-world study still confirms that EloPd is a safe and possible therapeutic choice for RRMM. Nevertheless, novel strategies are desirable for those patients exposed to daratumumab.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona , Mieloma Múltiplo , Talidomida , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Masculino , Feminino , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Pessoa de Meia-Idade , Talidomida/análogos & derivados , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/uso terapêutico , Estudos Retrospectivos , Seguimentos , Idoso de 80 Anos ou mais , Adulto , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Resistencia a Medicamentos Antineoplásicos , Taxa de SobrevidaRESUMO
BACKGROUND: Venetoclax in combination with hypomethylating agents (HMA) is revolutionizing the therapy of acute myeloid leukemia (AML). However, evidence on large sets of patients is lacking, especially in relapsed or refractory leukemia. METHODS: AVALON is a multicentric cohort study that was conducted in Italy on patients with AML who received venetoclax-based therapies from 2015 to 2020. The study was approved by the ethics committee of the participating institution and was conducted in accordance with the Declaration of Helsinki. The effectiveness and toxicity of venetoclax + HMA in 190 (43 newly diagnosed, 68 refractory, and 79 relapsed) patients with AML are reported here. RESULTS: In the newly diagnosed AML, the overall response rate and survival confirmed the brilliant results demonstrated in VIALE-A. In the relapsed or refractory AML, the combination demonstrated a surprisingly complete remission rate (44.1% in refractory and 39.7% in relapsed evaluable patients) and conferred to treated patients a good expectation of survival. Toxicities were overall manageable, and most incidents occurred in the first 60 days of therapy. Infections were confirmed as the most common nonhematologic adverse event. CONCLUSIONS: Real-life data show that the combination of venetoclax and HMA offers an expectation of remission and long-term survival to elderly, newly diagnosed patients, and to relapsed or chemoresistant AML, increasing the chance of cure through a different mechanism of action. The venetoclax + HMA combination is expected to constitute the base for triplet combinations and integration of target therapies. Our data contribute to ameliorate the understanding of venetoclax + HMA effectiveness and toxicities in real life.
Assuntos
Leucemia Mieloide Aguda , Humanos , Idoso , Estudos de Coortes , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Sulfonamidas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Doxorubicin (Dox) is one of the most commonly used anthracyclines for the treatment of solid and hematological tumors such as B-/T cell acute lymphoblastic leukemia (ALL). Dox compromises topoisomerase II enzyme functionality, thus inducing structural damages during DNA replication and causes direct damages intercalating into DNA double helix. Eukaryotic cells respond to DNA damages by activating the ATM-CHK2 and/or ATR-CHK1 pathway, whose function is to regulate cell cycle progression, to promote damage repair, and to control apoptosis. We evaluated the efficacy of a new drug schedule combining Dox and specific ATR (VE-821) or CHK1 (prexasertib, PX) inhibitors in the treatment of human B-/T cell precursor ALL cell lines and primary ALL leukemic cells. We found that ALL cell lines respond to Dox activating the G2/M cell cycle checkpoint. Exposure of Dox-pretreated ALL cell lines to VE-821 or PX enhanced Dox cytotoxic effect. This phenomenon was associated with the abrogation of the G2/M cell cycle checkpoint with changes in the expression pCDK1 and cyclin B1, and cell entry in mitosis, followed by the induction of apoptosis. Indeed, the inhibition of the G2/M checkpoint led to a significant increment of normal and aberrant mitotic cells, including those showing tripolar spindles, metaphases with lagging chromosomes, and massive chromosomes fragmentation. In conclusion, we found that the ATR-CHK1 pathway is involved in the response to Dox-induced DNA damages and we demonstrated that our new in vitro drug schedule that combines Dox followed by ATR/CHK1 inhibitors can increase Dox cytotoxicity against ALL cells, while using lower drug doses. ⢠Doxorubicin activates the G2/M cell cycle checkpoint in acute lymphoblastic leukemia (ALL) cells. ⢠ALL cells respond to doxorubicin-induced DNA damages by activating the ATR-CHK1 pathway. ⢠The inhibition of the ATR-CHK1 pathway synergizes with doxorubicin in the induction of cytotoxicity in ALL cells. ⢠The inhibition of ATR-CHK1 pathway induces aberrant chromosome segregation and mitotic spindle defects in doxorubicin-pretreated ALL cells.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteínas Quinases , Humanos , Proteínas Quinases/metabolismo , Quinase 1 do Ponto de Checagem/genética , Quinase 1 do Ponto de Checagem/metabolismo , Doxorrubicina/farmacologia , Dano ao DNA , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismoRESUMO
PURPOSE: CAR-T programs will burden increasingly on healthcare systems, since the implementation of these therapies involves: multidisciplinary team collaboration, post-infusion hospitalization with risk of life-threatening toxicities, frequent in hospital visits and prolonged follow-up which heavily influence patients' quality of life. In this review we propose an innovative, telehealth-based, model for monitoring CAR-T patients: this method was used for managing a case of COVID-19 infection occurred two weeks after CAR-T cell infusion. METHODS: Several benefits for management of all these aspects of CAR-T programs could be made using telemedicine: for example, telemedicine real-time clinical monitoring could reduce the COVID-19 contagion risks for CAR-T patients. RESULTS: Our experience confirmed feasibility and utility of this approach in a real-life case. We believe that use of telemedicine for CAR-T patients could improve: the logistics of toxicity monitoring (frequent vital sign checks and neurologic assessments), the multidisciplinary team communication (patient selection, specialists consulting, coordination with pharmacists, etc.), the decrease in hospitalization time and the reduction of ambulatory visits. CONCLUSIONS: This approach will be fundamental for future CAR-T cell program development, enhancing patients' quality of life and cost-effectiveness for healthcare systems.
Assuntos
COVID-19 , Receptores de Antígenos Quiméricos , Telemedicina , Humanos , Pandemias/prevenção & controle , Qualidade de Vida , Terapia Baseada em Transplante de Células e TecidosRESUMO
The treatment scenario for newly-diagnosed transplant-ineligible multiple myeloma patients (NEMM) is quickly evolving. Currently, combinations of proteasome inhibitors and/or immunomodulatory drugs +/- the monoclonal antibody Daratumumab are used for first-line treatment, even if head-to-head comparisons are lacking. To compare efficacy and safety of these regimens, we performed a network meta-analysis of 27 phase 2/3 randomized trials including a total of 12,935 patients and 23 different schedules. Four efficacy/outcome and one safety indicators were extracted and integrated to obtain (for each treatment) the surface under the cumulative ranking-curve (SUCRA), a metric used to build a ranking chart. With a mean SUCRA of 83.8 and 80.08 respectively, VMP + Daratumumab (DrVMP) and Rd + Daratumumab (DrRd) reached the top of the chart. However, SUCRA is designed to work for single outcomes. To overcome this limitation, we undertook a dimensionality reduction approach through a principal component analysis, that unbiasedly grouped the 23 regimens into three different subgroups. On the bases of our results, we demonstrated that first line treatment for NEMM should be based on DrRd (most active, but continuous treatment), DrVMP (quite "fixed-time" treatment), or, alternatively, VRD and that, surprisingly, melphalan as well as Rd doublets still deserve a role in this setting.
Assuntos
Mieloma Múltiplo , Humanos , Metanálise em Rede , Mieloma Múltiplo/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The combination of elotuzumab, lenalidomide, and dexamethasone (EloRd) enhanced the clinical benefit over Rd with a manageable toxicity profile in the ELOQUENT-2 trial, leading to its approval in relapsed/refractory multiple myeloma (RRMM). The present study is a 3-year follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloRd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 36 months (range 6-55), 236 patients experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 18.4 and 34 months, respectively. The updated multivariate analyses showed a significant reduction of PFS and OS benefit magnitude only in cases with International Staging System stage III. Major adverse events included grade 3/4 neutropenia (18.5%), anemia (15.4%), lymphocytopenia (12.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 33.9% and 18.9%, respectively. No new safety signals with longer follow-up have been observed. Of 319 patients, 245 (76.7%) reached at least a partial remission. A significantly lower response rate was found in patients previously exposed to lenalidomide. In conclusion, our study confirms that EloRd is a safe and effective regimen for RRMM patients, maintaining benefits across multiple unfavorable subgroups.
Assuntos
Mieloma Múltiplo , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Seguimentos , Humanos , Lenalidomida/uso terapêutico , Estudos Retrospectivos , Talidomida/efeitos adversosRESUMO
INTRODUCTION: New treatments have improved the overall survival of patients with multiple myeloma (MM). At diagnosis and during the course of the disease, patients often report pain and other symptoms. Given the long disease trajectory, psychological and social issues are also frequent. Recently, the potential usefulness of early palliative care (EPC) was hypothesized in the area of hematology. We conducted a retrospective analysis of patients with MM referred to our institute for a palliative care (PC) consultation between January 2017 and June 2020. Our aim was to evaluate the main reasons (pain or other clinical symptoms) for the referral for a first PC consultation. METHODS: We examined the main reasons for the first PC consultation, the number of PC consultations carried out, and the period of time between diagnosis, first and subsequent PC visits, and death. We also recorded information on the type of pain experienced and the treatments administered. RESULTS: Of the 325 patients with MM followed at our hematology unit during the study period, 43 were referred for a PC consultation (39 for pain management and 4 to determine the most appropriate care setting (hospice or palliative homecare service)). Nineteen (44.2%) of the 43 patients reported other symptoms in addition to pain. The median time between MM diagnosis and the first PC consultation was 473 days. Fifteen patients died, with a median 332 days between the first PC visit and death. CONCLUSION: Randomized studies on MM involving larger patient populations with access to EPC are needed to identify an effective clinical model to improve the management of patients with MM.
Assuntos
Cuidados Paliativos na Terminalidade da Vida , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Cuidados Paliativos , Encaminhamento e Consulta , Estudos RetrospectivosRESUMO
The treatment landscape for hematologic malignancies has changed since the recent approval of highly effective chimeric antigen receptor T-cell therapies (CAR-T). Moreover, more than 600 active trials are currently ongoing. However, early enthusiasm should be tempered since several issues are still unsolved and represent the challenges for the coming years. The lack of initial responses and early relapse are some hurdles to be tackled. Moreover, new strategies are needed to increase the safety profile or shorten the manufacturing process during CAR-T cells therapy production. Nowadays, most clinically evaluated CAR-T cells products are derived from autologous immune cells. The use of allogeneic CAR-T cells products generated using cells from healthy donors has the potential to change the scenario and overcome many of these limitations. In addition, CAR-T cells carry a high price tag, and there is an urgent need to understand how to pay for these therapies as many of today's current payment systems do not feature the functionality to address the reimbursement gap. Finally, the clinical experience with CAR-T cells for solid tumors has been less encouraging, and development in this setting is desirable.
Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T , Recidiva Local de Neoplasia/tratamento farmacológico , Imunoterapia Adotiva , Neoplasias/tratamento farmacológico , Terapia Baseada em Transplante de Células e TecidosRESUMO
The immune system is a dynamic feature of each individual and a footprint of our unique internal and external exposures. Indeed, the type and level of exposure to physical and biological agents shape the development and behavior of this complex and diffuse system. Many pathological conditions depend on how our immune system responds or does not respond to a pathogen or a disease or on how the regulation of immunity is altered by the disease itself. T-cells are important players in adaptive immunity and, together with B-cells, define specificity and monitor the internal and external signals that our organism perceives through its specific receptors, TCRs and BCRs, respectively. Today, high-throughput sequencing (HTS) applied to the TCR repertoire has opened a window of opportunity to disclose T-cell repertoire development and behavior down to the clonal level. Although TCR repertoire sequencing is easily accessible today, it is important to deeply understand the available technologies for choosing the best fit for the specific experimental needs and questions. Here, we provide an updated overview of TCR repertoire sequencing strategies, providers and applications to infectious diseases and cancer to guide researchers' choice through the multitude of available options. The possibility of extending the TCR repertoire to HLA characterization will be of pivotal importance in the near future to understand how specific HLA genes shape T-cell responses in different pathological contexts and will add a level of comprehension that was unthinkable just a few years ago.
Assuntos
Doenças Transmissíveis , Neoplasias , Linfócitos B , Doenças Transmissíveis/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias/genética , Receptores de Antígenos de Linfócitos T/genética , Linfócitos TRESUMO
Multiple myeloma (MM) survival rates have been substantially increased thanks to novel agents that have improved survival outcomes and shown better tolerability than treatments of earlier years. These new agents include immunomodulating imide drugs (IMiD) thalidomide and lenalidomide, the proteasome inhibitor bortezomib (PI), recently followed by new generation IMID pomalidomide, monoclonal antibodies daratumumab and elotuzumab, and next generation PI carfilzomib and ixazomib. However, even in this more promising scenario, febrile neutropenia remains a severe side effect of antineoplastic therapies and can lead to a delay and/or dose reduction in subsequent cycles. Supportive care has thus become key in helping patients to obtain the maximum benefit from novel agents. Filgrastim is a human recombinant subcutaneous preparation of G-CSF, largely adopted in hematological supportive care as "on demand" (or secondary) prophylaxis to recovery from neutropenia and its infectious consequences during anti-myeloma treatment. On the contrary, pegfilgrastim is a pegylated long-acting recombinant form of granulocyte colony-stimulating factor (G-CSF) that, given its extended half-life, can be particularly useful when adopted as "primary prophylaxis," therefore before the onset of neutropenia, along chemotherapy treatment in multiple myeloma patients. There is no direct comparison between the two G-CSF delivery modalities. In this review, we compare data on the two administrations' modality, highlighting the efficacy of the secondary prophylaxis over multiple myeloma treatment. Advantage of pegfilgrastim could be as follows: the fixed administration rather than multiple injections, reduction in neutropenia and febrile neutropenia rates, and, finally, a cost-effectiveness advantage.
Assuntos
Neutropenia Febril , Mieloma Múltiplo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neutropenia Febril/induzido quimicamente , Neutropenia Febril/prevenção & controle , Filgrastim , Fator Estimulador de Colônias de Granulócitos , Humanos , Mieloma Múltiplo/tratamento farmacológico , Polietilenoglicóis , Proteínas RecombinantesRESUMO
INTRODUCTION: Treatment of relapsed and refractory (R/R) B acute lymphoblastic leukemia (B-ALL) represents an unmet medical need in children and adults. Adoptive T cells engineered to express a chimeric antigen receptor (CAR-T) is emerging as an effective technique for treating these patients. Areas covered: Efficacy and safety of CAR-T therapy in R/R B-ALL patients. Expert opinion: CD19 CAR-T infusion induce high CR rates in patients with poor prognosis and few therapeutic options, while real-life data demonstrate similar results with an interestingly lower incidence of grade 3/4 toxicity. Nevertheless, despite impressive in-depth responses, more than half of patients will experience a relapse. Therefore, rather than using CAR-T cell therapy as a stand-alone option, consolidation with allogeneic stem-cell transplant (Allo-SCT) after CAR-T treatment might increase long-term outcome. Moreover, CD19 is one target, but several other targets are being examined, such as CD20 and CD22 and dual-targeting CARs or combination therapy. Another issue is the time consuming process of CAR-T engineering. New platforms have shortened the CAR-T cell manufacturing process, and studies are underway to evaluate the effectiveness. Another way to mitigate waiting is the development of allogeneic "off the shelf" therapy. In conclusion, CD19-targeted CAR-modified T-cell therapy has shown unprecedented results in patients without curative options. Future work focusing on target identification, toxicity management and reducing manufacturing time will broaden the clinical applicability and bring this exciting therapy to more patients, with longer-term remissions without additional Allo-SCT.
Assuntos
Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Animais , Antígenos CD19/imunologia , Ensaios Clínicos como Assunto , Transplante de Células-Tronco Hematopoéticas , Humanos , Resultado do TratamentoRESUMO
Cytarabine, the 4-amino-1-(ß-D-arabinofuranosyl)-2(1H)-pyrimidinone, (ARA-C) is an antimetabolite cytidine analogue used worldwide as key drug in the management of leukaemia. As specified in the manufacturers' instructions, once the components-sterile water and cytarabine powder-are unpackaged and mixed, the solution begins to degrade after 6 hours at room temperature and 12 hours at 4°C. To evaluate how to avoid wasting the drug in short-term, low-dose treatment regimens, the reconstituted samples, stored at 25°C and 4°C, were analyzed every day of the test week by reversed-phase HPLC and high-field NMR spectroscopy. All the samples remained unchanged for the entire week, which corresponds to the time required to administer the entire commercial drug package during low-dose therapeutic regimens. The drug solution was stored in a glass container at 4°C in an ordinary freezer and drawn with sterile plastic syringes; during this period, no bacterial or fungal contamination was observed. Our findings show that an cytarabine solution prepared and stored in the original vials retains its efficacy and safety and can, therefore, be divided into small doses to be administered over more days, thus avoiding unnecessary expensive and harmful waste of the drug preparation. Moreover, patients who require daily administration of the drug could undergo the infusion at home without need to go to hospital. The stability of the aliquots would help decrease hospitalization costs.
Assuntos
Citarabina/química , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/economia , Cromatografia Líquida de Alta Pressão , Redução de Custos , Citarabina/administração & dosagem , Citarabina/economia , Custos de Medicamentos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Adesão à Medicação , Ressonância Magnética Nuclear Biomolecular/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Soluções/químicaRESUMO
The optimal first-line treatment for advanced-stage Hodgkin's lymphoma (HL) is still a matter of debate. While ABVD is less toxic and as effective as other, more intensive chemotherapy regimens, escalated BEACOPP (BEACOPPesc) is superior to ABVD for initial disease control and prolonged time-to-relapse. However, this advantage is associated with higher rate of early and late toxicities. As most of these data have been accumulated from clinical trials, a retrospective analysis was conducted in a large database of patients treated outside clinical trials to investigate the advantages and disadvantages of these regimes in a real-world setting. From October 2009 to October 2018, 397 advanced-stage HL patients treated with either ABVD or BEACOPPesc were retrospectively assessed in 7 European cancer centers (2 Austrian and 5 Italian centers). Complete metabolic remission (CMR) by PET was achieved in 76% and 85% of patients in the ABVD and BEACOPPesc groups, respectively (p = .01). Severe adverse events occurred more frequently with BEACOPPesc than ABVD. At a median follow-up of 8 years, 9% of the patients who achieved CMR after BEACOPPesc relapsed compared to 16.6% in the ABVD group (p = .043). No statistical difference in progression free survival (PFS) was observed between the two cohorts overall (p = .11), but there was a trend towards a superior PFS in high-risk patients treated with BEACOPPesc (p = .074). Nevertheless, overall survival was similar between the two groups (p = .94). In conclusion, we confirm that ABVD is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control, the long-term outcome remains similar between the two regimens.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doença de Hodgkin , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Áustria , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Seguimentos , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/mortalidade , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Procarbazina/administração & dosagem , Procarbazina/efeitos adversos , Taxa de Sobrevida , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
BACKGROUND: Rituximab plus bendamustine (R-B) has been demonstrated to improve outcomes and reduce toxicity compared with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) in follicular lymphoma (FL). Nevertheless, in clinical practice, many centers still prefer R-CHOP to R-B in patients with FL grade 3A (FL3A). Therefore, we retrospectively assessed patients with FL3A treated with either R-CHOP or R-B in five European cancer centers and compared their outcomes. MATERIALS AND METHODS: We retrospectively assessed 132 patients affected by FL grade 3A treated with either R-B or R-CHOP in the first line and evaluated outcome and toxicity according to the type of treatment. This study included 101 patients who were a subgroup of a previously published cohort. RESULTS: R-B was less toxic and achieved a similar percentage of complete remissions compared with R-CHOP (97% vs. 96%, p = .3). During follow-up, 10 (16%) patients relapsed after R-B and 29 (41%) after R-CHOP (p = .001), leading to a median progression-free survival (PFS) of 15 versus 11.7 years, respectively (p = .03). Furthermore, R-B overcame the negative prognostic impact of BCL2 expression (15 vs. 4.8 years; p = .001). However, median overall survival was similar between both groups (not reached for both; p = .8). CONCLUSION: R-B as a first-line treatment of FL3A is better tolerated than R-CHOP and seems to induce more profound responses, leading to a significantly lower relapse rate and prolonged PFS. Therefore, R-B is a valid treatment option for FL grade 3A. IMPLICATIONS FOR PRACTICE: Rituximab plus bendamustine (R-B) has shown to be less toxic and more effective than rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) in follicular lymphoma grade 3A. Although both regimens can induce a complete remission in >95% of patients, relapses occur more frequently after R-CHOP than R-B, leading to a significantly longer progression-free survival in the latter. R-B is also able to overcome the impact of negative prognosticators, such as BCL2 expression. However, because of the indolent course of this disease and efficient salvage treatments, overall survival was similar in both treatment groups. Therefore, R-B is a valid treatment option in this patient setting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Rituximab/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/efeitos adversos , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Humanos , Linfoma Folicular/metabolismo , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Pessoa de Meia-Idade , Gradação de Tumores , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Estudos Retrospectivos , Rituximab/efeitos adversos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Recent reports identify NLR (the ratio between absolute neutrophils counts, ANC, and absolute lymphocyte count, ALC), as predictor of progression-free survival (PFS) and overall survival (OS) in cancer patients. We retrospectively tested NLR and LMR (the ratio between absolute lymphocyte and monocyte counts) in newly diagnosed Hodgkin lymphoma (HL) patients treated upfront with a PET-2 risk-adapted strategy. NLR and LMR were calculated using records obtained from the complete blood count (CBC) from 180 newly diagnosed HL patients. PFS was evaluated accordingly to Kaplan-Meier method. Higher NLR was associated to advanced stage, increased absolute counts of neutrophils and reduced count of lymphocytes, and markers of systemic inflammation. After a median follow-up of 68 months, PFS at 60 months was 86.6% versus 70.1%, respectively, in patients with NLR ≥ 6 or NLR < 6. Predictors of PFS at 60 months were PET-2 scan (p < 0.0001), NLR ≥ 6.0 (p = 0.02), LMR < 2 (p = 0.048), and ANC (p = 0.0059) in univariate analysis, but only PET-2 was an independent predictor of PFS in multivariate analysis. Advanced-stage patients (N = 119) were treated according to a PET-2 risk-adapted protocol, with an early switch to BEACOPP regimen in case of PET-2 positivity. Despite this strategy, patients with positive PET-2 still had an inferior outcome, with PFS at 60 months of 84.7% versus 40.1% (negative and positive PET-2 patients, respectively, p < 0.0001). Independent predictors of PFS by multivariate analysis were PET-2 status and to a lesser extend NLR in advanced stage, while LMR maintained its significance in early stage. By focusing on PET-2 negative patients, we found that patients with NLR ≥ 6.0 or LMR < 2 had an inferior outcome compared to patients with both ratios above the cutoff (78.7 versus 91.9 months, p = 0.01). We confirm NLR as predictor of PFS in HL patients independently from stage at diagnosis. Integration of PET-2 scan, NLR and LMR can result in a meaningful prognostic system that needs to be further validated in prospective series including patients treated upfront with PET-2 adapted-risk therapy.
Assuntos
Doença de Hodgkin/diagnóstico por imagem , Linfócitos/imunologia , Monócitos/imunologia , Neutrófilos/imunologia , Adolescente , Adulto , Idoso , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/uso terapêutico , Contagem de Células Sanguíneas , Estudos de Coortes , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Seguimentos , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/imunologia , Doença de Hodgkin/patologia , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Prednisona/uso terapêutico , Procarbazina/uso terapêutico , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Vincristina/uso terapêutico , Adulto JovemRESUMO
Renal impairment (RI) is a relevant complication of patients affected by multiple myeloma (MM); it can be present in up to 30-35% of newly diagnosed MM and is linked to a poor outcome. However, early recognition and early treatment with novel agents can overcome the negative impact of RI and even reverse kidney damage in most cases. Lenalidomide, available as an oral compound, is an immunomodulatory drug with both antiproliferative and immunomodulatory activity that is largely used in the management of MM. Dose reduction is mandatory in RI; however, there is no theoretical assumption against the possibility that protracting the time of full standard doses can be equally effective and tolerated by patients requiring reduced doses. In this report, we describe our retrospective experience, in 18 patients, with the administration of lenalidomide 25 mg every other day for patients with MM and RI. The overall response ratio was 66.5%. More than half (61.1%) of the patients had a renal response. The median progression-free survival was 8 months (range: 3-18 months). No serious adverse event occurred during treatment, and it was never necessary to disrupt or delay treatment for toxicity. These preliminary observations point to a significant therapeutic effect of lenalidomide, at the dose of 25 mg every other day for 21 days, with logistic and economic advantages. However, these results should be validated by controlled studies involving larger numbers of patients.
Assuntos
Fatores Imunológicos/uso terapêutico , Imunomodulação , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Insuficiência Renal/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Lenalidomida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/imunologia , Intervalo Livre de Progressão , Insuficiência Renal/etiologia , Estudos RetrospectivosRESUMO
Despite novel agents, multiple myeloma is still an incurable disease, especially for elderly and frail patients, who are difficult to manage for concomitant comorbidities as the therapeutic options are limited and the response to chemotherapy is often short. We report our evaluations upon safety and efficacy of domestic subcutaneous bortezomib in elderly and frail patients candidate to bortezomib-melphalan-prednisone (VMP) regimen. We confirmed that overall incidence of adverse events, including peripheral neuropathy, was low, and in no case required admission to emergency service, contributing to reduce the rate of therapy discontinuation. These results confirm the effectiveness and safety of subcutaneous bortezomib, in a real-life-experience, and define a new possibility of safe auto-administration in a comfortable domestic setting. We suggest that domestic treatment can significantly improve the quality of life of the patients, avoiding unnecessary transfer to the hospital without reducing treatment efficacy.