ABSTRACT
The consensus panel 2 (CP2) of the 11th International Workshop on Waldenström's macroglobulinemia (IWWM-11) has reviewed and incorporated current data to update the recommendations for treatment approaches in patients with relapsed or refractory WM (RRWM). The key recommendations from IWWM-11 CP2 include: (1) Chemoimmunotherapy (CIT) and/or a covalent Bruton tyrosine kinase (cBTKi) strategies are important options; their use should reflect the prior upfront strategy and are subject to their availability. (2) In selecting treatment, biological age, co-morbidities and fitness are important; nature of relapse, disease phenotype and WM-related complications, patient preferences and hematopoietic reserve are also critical factors while the composition of the BM disease and mutational status (MYD88, CXCR4, TP53) should also be noted. (3) The trigger for initiating treatment in RRWM should utilize knowledge of patients' prior disease characteristics to avoid unnecessary delays. (4) Risk factors for cBTKi related toxicities (cardiovascular dysfunction, bleeding risk and concurrent medication) should be addressed when choosing cBTKi. Mutational status (MYD88, CXCR4) may influence the cBTKi efficacy, and the role of TP53 disruptions requires further study) in the event of cBTKi failure dose intensity could be up titrated subject to toxicities. Options after BTKi failure include CIT with a non-cross-reactive regimen to one previously used CIT, addition of anti-CD20 antibody to BTKi, switching to a newer cBTKi or non-covalent BTKi, proteasome inhibitors, BCL-2 inhibitors, and new anti-CD20 combinations are additional options. Clinical trial participation should be encouraged for all patients with RRWM.
Subject(s)
Antineoplastic Agents , Waldenstrom Macroglobulinemia , Humans , Waldenstrom Macroglobulinemia/drug therapy , Waldenstrom Macroglobulinemia/genetics , Myeloid Differentiation Factor 88/genetics , Consensus , Neoplasm Recurrence, Local/chemically induced , Neoplasm Recurrence, Local/drug therapy , Antineoplastic Agents/therapeutic useABSTRACT
Apart from the MYD88L265P mutation, extensive information exists on the molecular mechanisms in Waldenström's Macroglobulinemia and its potential utility in the diagnosis and treatment tailoring. However, no consensus recommendations are yet available. Consensus Panel 3 (CP3) of the 11th International Workshop on Waldenström's Macroglobulinemia (IWWM-11) was tasked with reviewing the current molecular necessities and best way to access the minimum data required for a correct diagnosis and monitoring. Key recommendations from IWWM-11 CP3 included: (1) molecular studies are warranted for patients in whom therapy is going to be started; such studies should also be done in those whose bone marrow (BM) material is sampled based on clinical issues; (2) molecular studies considered essential for these situations are those that clarify the status of 6q and 17p chromosomes, and MYD88, CXCR4, and TP53 genes. These tests in other situations, and/or other tests, are considered optional; (3) independently of the use of more sensitive and/or specific techniques, the minimum requirements are allele specific polymerase chain reaction for MYD88L265P and CXCR4S338X using whole BM, and fluorescence in situ hybridization for 6q and 17p and sequencing for CXCR4 and TP53 using CD19+ enriched BM; (4) these requirements refer to all patients; therefore, sample should be sent to specialized centers.
Subject(s)
Waldenstrom Macroglobulinemia , Humans , Waldenstrom Macroglobulinemia/diagnosis , Waldenstrom Macroglobulinemia/genetics , Waldenstrom Macroglobulinemia/therapy , Myeloid Differentiation Factor 88/genetics , In Situ Hybridization, Fluorescence , MutationABSTRACT
Consensus Panel 5 (CP5) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11; held in October 2022) was tasked with reviewing the current data on the coronavirus disease-2019 (COVID-19) prophylaxis and management in patients with Waldenstrom's Macroglobulinemia (WM). The key recommendations from IWWM-11 CP5 included the following: Booster vaccines for SARS-CoV-2 should be recommended to all patients with WM. Variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4.5 strain, are important as novel mutants emerge and become dominant in the community. A temporary interruption in Bruton's Tyrosine Kinase-inhibitor (BTKi) or chemoimmunotherapy before vaccination might be considered. Patients under treatment with rituximab or BTK-inhibitors have lower antibody responses against SARS-CoV-2; thus, they should continue to follow preventive measures, including mask wearing and avoiding crowded places. Patients with WM are candidates for preexposure prophylaxis, if available and relevant to the dominant SARS-CoV-2 strains in a specific area. Oral antivirals should be offered to all symptomatic WM patients with mild to moderate COVID-19 regardless of vaccination, disease status or treatment, as soon as possible after the positive test and within 5 days of COVID-19-related symptom onset. Coadministration of ibrutinib or venetoclax with ritonavir should be avoided. In these patients, remdesivir offers an effective alternative. Patients with asymptomatic or oligosymptomatic COVID-19 should not interrupt treatment with a BTK inhibitor. Infection prophylaxis is essential in patients with WM and include general preventive measures, prophylaxis with antivirals and vaccination against common pathogens including SARS-CoV-2, influenza, and S. pneumoniae.
Subject(s)
COVID-19 , Waldenstrom Macroglobulinemia , Humans , Waldenstrom Macroglobulinemia/drug therapy , Waldenstrom Macroglobulinemia/prevention & control , Waldenstrom Macroglobulinemia/diagnosis , COVID-19 Vaccines , Consensus , SARS-CoV-2 , Antiviral Agents/therapeutic useABSTRACT
Recent advances in the understanding of Waldenström macroglobulinemia (WM) biology have impacted the development of effective novel agents and improved our knowledge of how the genomic background of WM may influence selection of therapy. Consensus Panel 7 (CP7) of the 11th International Workshop on WM was convened to examine the current generation of completed and ongoing clinical trials involving novel agents, consider updated data on WM genomics, and make recommendations on the design and prioritization of future clinical trials. CP7 considers limited duration and novel-novel agent combinations to be the priority for the next generation of clinical trials. Evaluation of MYD88, CXCR4 and TP53 at baseline in the context of clinical trials is crucial. The common chemoimmunotherapy backbones, bendamustine-rituximab (BR) and dexamethasone, rituximab and cyclophosphamide (DRC), may be considered standard-of-care for the frontline comparative studies. Key unanswered questions include the definition of frailty in WM; the importance of attaining a very good partial response or better (≥VGPR), within stipulated time frame, in determining survival outcomes; and the optimal treatment of WM populations with special needs.
Subject(s)
Waldenstrom Macroglobulinemia , Humans , Waldenstrom Macroglobulinemia/drug therapy , Waldenstrom Macroglobulinemia/genetics , Rituximab/therapeutic use , Consensus , Cyclophosphamide/therapeutic use , Bendamustine Hydrochloride/therapeutic useABSTRACT
BACKGROUND: The COVID-19 pandemic has created enormous challenges for the clinical management of patients with hematological malignancies (HMs), raising questions about the optimal care of this patient group. METHODS: This consensus manuscript aims at discussing clinical evidence and providing expert advice on statements related to the management of HMs in the COVID-19 pandemic. For this purpose, an international consortium was established including a steering committee, which prepared six working packages addressing significant clinical questions from the COVID-19 diagnosis, treatment, and mitigation strategies to specific HMs management in the pandemic. During a virtual consensus meeting, including global experts and lead by the European Society for Medical Oncology and the European Hematology Association, statements were discussed and voted upon. When a consensus could not be reached, the panel revised statements to develop consensual clinical guidance. RESULTS AND CONCLUSION: The expert panel agreed on 33 statements, reflecting a consensus, which will guide clinical decision making for patients with hematological neoplasms during the COVID-19 pandemic.
Subject(s)
COVID-19 , Hematologic Neoplasms , Humans , Consensus , COVID-19 Testing , Hematologic Neoplasms/epidemiology , Hematologic Neoplasms/therapy , PandemicsABSTRACT
BACKGROUND: Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is the recommended approach in patients with advanced epithelial ovarian cancer (EOC). However, most patients eventually relapse despite the initial high response rate to chemotherapy. Neutrophil-to-lymphocyte ratio is a well-known biomarker that reflects severe inflammation, critical illness, and mortality in various diseases. Chemotherapy response score (CRS) and neutrophil-to-lymphocyte ratio (NLR) have been identified as potential biomarkers of platinum resistance and disease prognosis. We retrospectively evaluated 132 patients with stage IIIc or IV ovarian/fallopian tube/primary peritoneal cancer who had received NACT followed by IDS from 01/01/2003 to 31/12/2018. CRS was assessed on omental specimens collected from IDS according to ICCR guidelines. RESULTS: Median age was 64.57 years (SD: 9.72; range 39.2-87.1). Most ovarian tumors were serous epithelial (90.9%; 120/132). An elevated NLR (defined as > 3) was observed in 72% (95/132) of patients in contrast with 28% (37/132) of patients characterized by low NLR status. Median PFS (mPFS) and median overall survival (mOS) were 13.05 months (95% CI: 11.42-14.67)) and 34.69 months (95% CI: 23.26-46.12) respectively. In univariate analysis, CRS3 score was significantly associated with prolonged mPFS (CRS1/2: 12.79 months vs CRS3: 17.7 months; P = 0.008). CRS score was not associated with mOS (P = 0.876). High NLR was not significantly associated with mPFS (P = 0.128), however it was significantly associated with poor mOS (P = 0.012). In multivariate analysis, only performance of surgery maintained its statistical significance with both PFS (P = 0.001) and OS (P = 0.008). CONCLUSION: NLR could serve as a useful predictor of OS but not PFS in ovarian cancer patients receiving NACT. In accordance with our previous study, CRS score at omentum was found to be associated with PFS but not OS in ovarian cancer patients treated with NACT and IDS.
Biomarkers that would predict response to neoadjuvant chemotherapy in advanced ovarian cancer patients are eagerly needed:⢠Neutrophil to Lymphocyte Ratio (NLR) is an indicator of systemic inflammatory response to the malignancy.⢠NLR was evaluated in 132 patients undergoing Neoadjuvant Chemotherapy for advanced ovarian cancer.⢠Elevated NLR was associated with worse prognosis.⢠No association between NLR and response to chemotherapy was noted.
Subject(s)
Lymphocytes/metabolism , Neutrophils/metabolism , Ovarian Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Female , Humans , Middle Aged , Ovarian Neoplasms/pathology , PrognosisABSTRACT
BACKGROUND: Immune checkpoint inhibitors have been widely implemented in current clinical practice. Although cancer occurs in â¼1 out of 1000 pregnancies, treatment remains challenging. Until now, limited data exist regarding immunotherapy administration during pregnancy. This systemic review aims to synthesize all available data from immunotherapy administration in pregnant women and evaluate the efficacy and safety of immunotherapy during pregnancy. PATIENTS AND METHODS: Eligible studies were identified by a search of the PubMed Medline database and Food and Drug Administration Adverse Events Reporting System Public Dashboard for the period 1 January 2000 to 1 April 2021; the algorithm consisted of a predefined combination of the words 'immunotherapy', 'cancer' and 'pregnancy'. PRISMA guidelines were applied in this study. RESULTS: Overall, seven articles (seven pregnancies, nine neonates) were retrieved. The mean duration of immunotherapy administration was 9.8 weeks [standard deviation (SD): 11.27; median: 7.0; range: 1-32]. In all cases specified, melanoma was the malignancy reported. The mean gestational age at delivery was 30.4 weeks (SD: 5.03; median: 32.0; range: 24-38), whereas the mean weight of neonates at delivery was 1267 g (SD: 412.0; median: 1400; range: 590-1701). Only one neonate was born term at 38 weeks of pregnancy (11.1%; 1/9). Complications during pregnancy were observed in 71.4% of cases: intrauterine growth restriction (three cases), HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count) (one case), placental insufficiency (one case) and low fetal heart rate (one case). The mean progression-free survival and overall survival were 16.0 and 25.2 months, respectively. CONCLUSION: The administration of immune checkpoint inhibitors during pregnancy is associated with increased incidence of pregnancy complications, prematurity and low birth weight. The administration of these regimens is not recommended during gestation. Whenever applied, close monitoring of the mother and the fetus is required.
Subject(s)
HELLP Syndrome , Pregnancy Complications , Female , Gestational Age , Humans , Immune Checkpoint Inhibitors , Infant, Newborn , Placenta , Pregnancy , United StatesABSTRACT
Immune checkpoint inhibitors (ICIs) are antibodies that target certain immune checkpoints (ICs), such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1) or its ligand (PD-L1), and have emerged as a powerful new tool for oncologists. As these immune checkpoints are crucial for immunological self-tolerance, such therapies can trigger autoimmune adverse effects. Endocrine complications are among the most common, including hypophysitis, thyroid dysfunction, diabetes mellitus and primary adrenal insufficiency, while autoimmune polyendocrine syndrome type 2 (APS-2) may also present. The aim of this article is to critically appraise the literature and present (i) the biological role and function of the main ICs, (ii) the use of ICIs in the treatment of various cancer types, (iii) the endocrine complications of cancer immunotherapy with ICIs and (iv) practical recommendations for screening and management of patients with such endocrinopathies in everyday clinical practice.
Subject(s)
Endocrine System Diseases , Hypophysitis , Endocrine System , Endocrine System Diseases/chemically induced , Humans , Hypophysitis/chemically induced , Immune Checkpoint Inhibitors , Immunotherapy/adverse effectsABSTRACT
BACKGROUND: Kidney cancer is a lethal neoplasm that affects several thousands of people every year. Renal cell carcinoma (RCC) is the most common histologic type. Recent developments in the therapeutic approach include antiangiogenic targeted approaches and Immunotherapy. Thus, the therapeutic algorithm of RCC patients and the survival outcomes have changed dramatically. METHODS: Herein we present a retrospective study of the patients treated in our Department with an antiangiogenic agent -Axitinib, a tyrosine kinase inhibitor- as a third or further line treatment. Statistical analysis was performed with SPSS, including the available clinicopathological data of the patients included. RESULTS: Axitinib was found to be active in patients who received this treatment beyond second line. The toxicity profile of this regimen did not reveal any unknown adverse events. CONCLUSIONS: Our real world data reflect that axitinib is a safe and effective option, even beyond the second line.
Subject(s)
Axitinib/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Adult , Aged , Female , Humans , Male , Middle Aged , Retrospective StudiesABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
BACKGROUND: The novel proteasome inhibitor carfilzomib alone or in combination with other agents is already one of the standard therapies for relapsed and/or refractory multiple myeloma (MM) patients and produces impressive response rates in newly diagnosed MM as well. However, carfilzomib-related cardiovascular adverse events (CVAEs) - including hypertension (all grades: 12.2%; grade ≥3: 4.3%), heart failure (all grades: 4.1%; grade ≥3: 2.5%) and ischemic heart disease (all grades: 1.8%; grade ≥3: 0.8%) - may lead to treatment suspensions. At present, there are neither prospective studies nor expert consensus on the prevention, monitoring and treatment of CVAEs in myeloma patients treated with carfilzomib. METHODS: An expert panel of the European Myeloma Network in collaboration with the Italian Society of Arterial Hypertension and with the endorsement of the European Hematology Association aimed to provide recommendations to support health professionals in selecting the best management strategies for patients, considering the impact on outcome and the risk-benefit ratio of diagnostic and therapeutic tools, thereby achieving myeloma response with novel combination approaches whilst preventing CVAEs. RESULTS: Patients scheduled to receive carfilzomib need a careful cardiovascular evaluation before treatment and an accurate follow-up during treatment. CONCLUSIONS: A detailed clinical assessment before starting carfilzomib treatment is essential to identify patients at risk for CVAEs, and accurate monitoring of blood pressure and of early signs and symptoms suggestive of cardiac dysfunction remains pivotal to safely administer carfilzomib without treatment interruptions or dose reductions.
Subject(s)
Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/therapy , Multiple Myeloma/drug therapy , Oligopeptides/adverse effects , Cardiovascular Diseases/chemically induced , Cardiovascular Diseases/prevention & control , Decision Trees , Humans , Monitoring, Physiologic , Oligopeptides/therapeutic useSubject(s)
Medical Oncology/standards , Neoplasm Recurrence, Local/therapy , Precision Medicine/standards , Societies, Medical/standards , Waldenstrom Macroglobulinemia/therapy , Aftercare/methods , Aftercare/standards , Age of Onset , Antineoplastic Combined Chemotherapy Protocols/standards , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Asymptomatic Diseases/therapy , Bone Marrow/pathology , Europe , Humans , Incidence , Medical Oncology/methods , Myeloid Differentiation Factor 88/genetics , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/epidemiology , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Plasmapheresis/methods , Plasmapheresis/standards , Precision Medicine/methods , Receptors, CXCR4/genetics , Stem Cell Transplantation/methods , Stem Cell Transplantation/standards , Survivorship , Transplantation, Autologous/methods , Transplantation, Autologous/standards , Treatment Outcome , Waldenstrom Macroglobulinemia/diagnosis , Waldenstrom Macroglobulinemia/epidemiology , Waldenstrom Macroglobulinemia/pathologyABSTRACT
During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drugs classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.Leukemia accepted article preview online, 18 December 2017. doi:10.1038/leu.2017.353.
ABSTRACT
Osteolytic bone disease is a frequent complication of multiple myeloma, resulting in skeletal complications that are a significant cause of morbidity and mortality. It is the result of an increased activity of osteoclasts, which is not followed by reactive bone formation by osteoblasts. Recent studies have revealed novel molecules and pathways that are implicated in osteoclast activation and osteoblast inhibition. Among them, the most important include the receptor activator of nuclear factor-kappa B ligand/osteoprotegerin pathway, the macrophage inflammatory proteins and the activin-A that play a crucial role in osteoclast stimulation in myeloma, while the wingless-type (Wnt) signalling inhibitors (sclerostin and dickkopf-1) along with the growth factor independence-1 are considered the most important factors for the osteoblast dysfunction of myeloma patients. Finally, the role of osteocytes, which is the key cell for normal bone remodelling, has also revealed during the last years through their interaction with myeloma cells that leads to their apoptosis and the release of RANKL and sclerostin maintaining bone loss in these patients. This review focuses on the latest available data for the mechanisms of bone destruction in multiple myeloma.
Subject(s)
Bone Resorption/physiopathology , Multiple Myeloma/physiopathology , Osteolysis/physiopathology , Adaptor Proteins, Signal Transducing , Apoptosis , Bone Morphogenetic Proteins/metabolism , Bone Resorption/etiology , Genetic Markers , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Multiple Myeloma/complications , Multiple Myeloma/metabolism , Osteoclasts/physiology , Osteocytes/physiology , Osteogenesis/physiology , Osteolysis/etiology , Osteolysis/metabolism , Osteoprotegerin/metabolism , RANK Ligand/metabolism , Wnt Signaling PathwayABSTRACT
Patients with multiple myeloma (MM) who undergo autologous stem cell transplantation (ASCT) are susceptible to severe infections. Low levels of circulating mannan-binding lectin (MBL) are associated with increased risk of infection. In this prospective study, we evaluated 100 patients who underwent ASCT regarding the effect of MBL on the incidence and severity of febrile episodes. Seventeen patients had MBL levels <500 ng/mL (11 received antibiotic prophylaxis and 6 did not). Although there was no statistical difference regarding the development of febrile episodes between patients with low and normal MBL, among 17 patients with low MBL levels, six out of eleven patients who received antibiotic prophylaxis developed a febrile episode compared with six out of six patients who did not receive antibiotic prophylaxis and developed a febrile episode. Patients with low MBL levels who responded less frequently to first line antibiotic therapy required more frequent administration of a second more advanced line of antibiotics, independently of receiving or not prophylaxis, and required prolonged hospitalization. In the univariate analysis low MBL associated with shorter OS. Our results suggest that patient with low MBL levels should receive antibiotic prophylaxis to reduce the number of febrile episodes and raise the issue of MBL replacement for these patients.