Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders

This is an open access paper.-- et al.The European Myeloma Network (EMN) organized two flow cytometry workshops. The first aimed to identify specific indications for flow cytometry in patients with monoclonal gammopathies, and consensus technical approaches through a questionnaire-based review of current practice in participating laboratories. The second aimed to resolve outstanding technical issues and develop a consensus approach to analysis of plasma cells. The primary clinical applications identified were: differential diagnosis of neoplastic plasma cell disorders from reactive plasmacytosis; identifying risk of progression in patients with MGUS and detecting minimal residual disease. A range of technical recommendations were identified, including: 1) CD38, CD138 and CD45 should all be included in at least one tube for plasma cell identification and enumeration. The primary gate should be based on CD38 vs. CD138 expression; 2) after treatment, clonality assessment is only likely to be informative when combined with immunophenotype to detect abnormal cells. Flow cytometry is suitable for demonstrating a stringent complete remission; 3) for detection of abnormal plasma cells, a minimal panel should include CD19 and CD56. A preferred panel would also include CD20, CD117, CD28 and CD27; 4) discrepancies between the percentage of plasma cells detected by flow cytometry and morphology are primarily related to sample quality and it is, therefore, important to determine that marrow elements are present in follow-up samples, particularly normal plasma cells in MRD negative cases.The meetings were sponsored by the European Myeloma.Peer Reviewe

Minimal residual disease is an independent predictor for 10-year survival in CLL

Minimal residual disease (MRD) negativity, defined as <1 chronic lymphocytic leukemia (CLL) cell detectable per 10 000 leukocytes, has been shown to independently predict for clinical outcome in patients receiving combination chemoimmunotherapy in the frontline setting. However, the long-term prognostic value of MRD status in other therapeutic settings remains unclear. Here, we retrospectively analyzed, with up to 18 years follow-up, all patients at our institution who achieved at least a partial response (PR) with various therapies between 1996 and 2007, and received a bone marrow MRD assessment at the end of treatment according to the international harmonized approach. MRD negativity correlated with both progression-free survival (PFS) and overall survival (OS) independent of the type and line of treatment, as well as known prognostic factors including adverse cytogenetics. The greatest impact of achieving MRD negativity was seen in patients receiving frontline treatment, with 10-year PFS of 65% vs 10% and 10-year OS of 70% vs 30% for MRD-negative vs MRD-positive patients, respectively. Our results demonstrate the long-term benefit of achieving MRD negativity, regardless of the therapeutic setting and treatment modality, and support its use as a prognostic marker for long-term PFS and as a potential therapeutic goal in CLL

Early emergence of CD19-negative human antibody secreting cells at the plasmablast to plasma cell transition

Long-lived human plasma cells (PCs) play central roles in immunity and autoimmunity and are enriched amongst the subpopulation of CD19-negative human PCs. However, whether human CD19-negative PCs are necessarily ″aged″ cells that have gradually lost CD19 expression is not known. Assessing peripheral blood samples at steady state and during the acute response to influenza vaccination in healthy donors we identify the presence of phenotypic CD19-negative plasmablasts, the proliferative precursor state to mature PCs, and demonstrate by ELISpot that these are antibody-secreting cells (ASCs). During the acute response to influenza vaccination CD19-positive, CD19-low and CD19-negative ASCs secrete vaccine-specific antibody and show linked IGHV repertoires. To address precursor/product relationships we employ in vitro models which mimic both T-dependent and T-independent differentiation finding that the CD19-negative state can be established at the plasmablast to PC transition, that CD19-negative PCs increase as a percentage of surviving PCs in vitro, and that CD19-negative and CD19-positive PCs can be maintained independently. These data provide proof-of-principle for the view that newly generated ASCs can acquire a mature PC phenotype accompanied by loss of CD19 expression at an early stage of differentiation and that ″aging″ is not an obligate requirement for a CD19-negative state to be established

GA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In CLL (GALACTIC) trial: study protocol for a phase II/III randomised controlled trial

Background: Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia. Achieving minimal residual disease (MRD) negativity in CLL is an independent predictor of survival even with a variety of different treatment approaches and regardless of the line of therapy. Methods/design: GA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In CLL (GALACTIC) is a seamless phase II/III, multi-centre, randomised, controlled, open, parallel-group trial for patients with CLL who have recently responded to chemotherapy. Participants will be randomised to receive either obinutuzumab (GA-101) consolidation or no treatment (as is standard). The phase II trial will assess safety and short-term efficacy in order to advise on continuation to a phase III trial. The primary objective for phase III is to assess the effect of consolidation therapy on progression-free survival (PFS). One hundred eighty-eight participants are planned to be recruited from forty research centres in the United Kingdom. Discussion: There is evidence that achieving MRD eradication with alemtuzumab consolidation is associated with improvements in survival and time to progression. This trial will assess whether obinutuzumab is safe in a consolidation setting and effective at eradicating MRD and improving PFS. Trial registration: ISRCTN, 64035629. Registered on 12 January 2015. EudraCT, 2014-000880-42. Registered on 12 November 2014

Assessment of ibrutinib plus rituximab in front-line CLL (FLAIR trial): study protocol for a phase III randomised controlled trial

Background Treatment of chronic lymphocytic leukaemia (CLL) has seen a substantial improvement over the last few years. Combination immunochemotherapy, such as fludarabine, cyclophosphamide and rituximab (FCR), is now standard first-line therapy. However, the majority of patients relapse and require further therapy, and so new, effective, targeted therapies that improve remission rates, reduce relapses, and have fewer side effects, are required. The FLAIR trial will assess whether ibrutinib plus rituximab (IR) is superior to FCR in terms of progression-free survival (PFS). Methods/design FLAIR is a phase III, multicentre, randomised, controlled, open, parallel-group trial in patients with previously untreated CLL. A total of 754 participants will be randomised on a 1:1 basis to receive standard therapy with FCR or IR. Participants randomised to FCR will receive a maximum of six 28-day treatment cycles. Participants randomised to IR will receive six 28-day cycles of rituximab, and ibrutinib taken daily for 6 years until minimal residual disease (MRD) negativity has been recorded for the same amount of time as it took to become MRD negative, or until disease progression. The primary endpoint is PFS according to the International Workshop on CLL (IWCLL) criteria. Secondary endpoints include: overall survival; proportion of participants with undetectable MRD; response to therapy by IWCLL criteria; safety and toxicity; health-related quality of life (QoL); and cost-effectiveness. Discussion The trial aims to provide evidence for the future first-line treatment of CLL patients by assessing whether IR is superior to FCR in terms of PFS, and whether toxicity rates are favourable. Trial registration ISRCTN01844152. Registered on 8 August 2014, EudraCT number 2013-001944-76. Registered on 26 April 2013

Doubling in median survival in patients diagnosed with multiple myeloma 2005-2019; a real-world study from the UK’s Haematological Malignancy Research Network

Recent decades have seen an explosion of therapeutic agents being evaluated in multiple myeloma (MM) clinical trials, and many of these have subsequently been licensed. Sadly, however, despite such advances, MM remains incurable. In addition, the restrictive inclusion and exclusion criteria of many clinical studies often mean that the beneficial effects seen within trials are not uniformly translated across the general patient population once agents are approved for use in routine clinical practice.1-3 Hence, understanding patterns of myeloma diagnosis and treatment in unselected real-world populations, and monitoring how they change over time in light of emerging therapeutic options, are key to informing clinical service strategy and clinical decision-making

COVID-19-related mortality in a real-world cohort of 18 883 patients with premalignant and malignant haematological neoplasms:An analysis from the UK's Haematological Malignancy Research Network

When the World Health Organization (WHO) declared the global COVID-19 pandemic, it was recognised that patients with haematological cancers would be more susceptible to severe disease. Set within a UK population of ~4 million (https://hmrn.org/), all patients diagnosed with haematological neoplasms 2005–2019 who were alive on 1 January 2020 were followed up until March 2023. For comparative purposes, a similar age- and sex-matched general population cohort was also constructed. COVID-19 deaths were classified using ICD-10 codes and a multiple cause of death analysis was undertaken using a competing risk approach. Deaths of 486/18 883 haematology patients were attributed to COVID-19, yielding a cumulative incidence of 2.59% (95% confidence interval [CI]: 2.37–2.82) that was significantly higher than that of the general population (1.65; 95% CI: 1.58–1.72). In both cohorts, risks were higher in men, older people and those with co-morbidities. Within the patient cohort, excess mortality was largely concentrated in those suffering from more indolent conditions. Patients with the premalignancy MBL suffered from the highest excess mortality in the early phase of the pandemic when, unlike patients with malignancies, they were not advised to shield. Effects of shielding were evident and a clear vaccination benefit was demonstrated, with the exception of CLL and MCL; findings that warrant consideration in relation to other viruses

Monoclonal B-cell lymphocytosis

AbstractThe incidence and presenting features of chronic lymphocytic leukemia (CLL) have changed significantly over the last century. Routine diagnostic techniques can now detect very low levels of CLL phenotype cells. Monoclonal B-cell lymphocytosis (MBL) is a relatively recent diagnostic category encapsulating individuals with an abnormal B-cell population but not meeting the diagnostic criteria for a B-cell malignancy. This review focuses on CLL-type MBL, which represents the majority of MBL cases identified in diagnostic laboratories. CLL-type MBL has a phenotype identical to CLL and shares the same chromosomal abnormalities even at the lowest levels detectable. Recent evidence suggests that the immunoglobulin gene usage plays a key role in whether the abnormal cells will develop in significant numbers. In most cases, CLL-type MBL is a stable condition with only 1% per year among those presenting for clinical attention developing progressive disease requiring treatment, although suppressed immune function may have a more significant impact on outcome.</jats:p