Reference: February 2024 | Issue 2 | Vol 10 | Page 29
The 65th American Society of Haematology Annual Meeting and Exposition took place 9-12 December 2023 in San Diego, California, US
Infections account for nearly half of all non-relapse mortality among patients with advanced blood cancers after treatment with CAR T-cell therapy
A recent meta-analysis of clinical trials and real-world studies presented at the American Society of Haematology Annual Meeting 2023 has found that infections were the primary cause of non-relapse mortality in patients who received treatment with any of the six chimeric antigen receptor (CAR) T-cell therapies currently approved by the US Food and Drug Administration (FDA).
The data also uncovered a high incidence of secondary malignancies that warrants “further systematic study”, according to the investigators.
Dr David Cordas dos Santos, Research Fellow at the Dana-Farber Cancer Institute, Boston, US, described CAR T-cell therapies as “practice-changing” in the management of relapsed/refractory B-cell malignancies, but highlighted that the treatment is associated with a distinct toxicity profile, and can also exert “profound and long-lasting immune deficits”.
Among all studies that met inclusion criteria, large B-cell lymphoma was the most common disorder, followed by multiple myeloma, mantle cell lymphoma, and indolent lymphomas, respectively. More than half of the studies did not report any measure of non-relapse mortality; therefore, investigators calculated a point estimate by dividing non-relapse related deaths by the total number of respective patients in the cohort.
Of note, the comparison showed that the point estimates and actual reported incidences differed by less than 1 per cent. All reported deaths were classified as either cytokine release syndrome (CRS), neurotoxicity, infection, haemorrhage, secondary malignancy, haemophagocytic lymphohistiocytosis (HLH), organ failure, not otherwise specified, or others/unknown.
In total, nearly half of all deaths were attributable to infections (47.6 per cent), while CRS, neurotoxicity, or HLH led to death in a total of 11.1 per cent of cases. Secondary malignancies were found to contribute to death in 6.1 per cent of cases, and haemorrhage in 3 per cent.
Dr De Santos noted that the Covid-19 pandemic must also be considered in analysing the findings, and advocated for more investigation, as well as high-quality, long-term reporting of non-relapse mortality. The FDA says the benefits of CAR T-cell therapy outweigh potential harms, but is investigating the risk of T-cell malignancy with serious outcomes, and is evaluating the need for regulatory action. It also states that clinical trial participants receiving the treatment should receive life-long monitoring for new malignancies.
Separate data also presented at the meeting shows that since the introduction of CAR T-cell therapy, there has been a “marked decline” in hematopoietic stem cell transplantation (HSCT) for advanced diffuse large B cell lymphoma, despite significantly improved outcomes in recent years.
Dr Philipp Berning, University Hospital Muenster, Germany, told attendees that CAR T-cell therapies have “challenged the role of auto- and allo-HSTC for the treatment of DLBCL”, while presenting findings from a Europe-based retrospective analysis of patients who received allo- and auto-HSCT.
MRD-directed ibrutinib-venetoclax improves outcomes in CLL as compared with chemoimmunotherapy
Attendees at the AmericanSociety of Haematology (ASH) Annual Meeting 2023 heard that in patients with untreated chronic lymphocytic leukaemia (CLL), administration of ibrutinib plus venetoclax for an individualised duration, rather than according to a fixed regime, had significantly better outcomes compared with conventional chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR).
Data from the phase 3, multicentre, randomised controlled trial was presented by Prof Peter Hillmen from the Leeds Institute of Medical Research at St James’s University Hospital, Leeds, UK, and showed meaningfully better progression-free and overall survival in the ibrutinib-venetoclax cohort.
The study is the third interim analysis of the National Cancer Research Institute FLAIR trial, an open-label, randomised, controlled, phase 3 trial in patients with previously untreated CLL across 101 UK National Health Service hospitals. The FLAIR trial has the potential to be practice changing.
The study, which was published in The New England Journal of Medicine, compared ibrutinib-venetoclax-ibrutinib with FCR in a total of 523 patients aged under 75, who were treated at 96 centres across the UK, and were randomly assigned to either group.
The duration of ibrutinib-venetoclax therapy was personalised according to measurable residual disease (MRD) assessed in peripheral blood and bone marrow. Patients in the FCR group received a conventional regime for six cycles. The primary end point was progression-free survival, while secondary endpoints were overall survival, response, MRD, and safety.
Describing the survival curves as “very impressive”, Prof Hillmen said that at a median of 43.7 months, disease progression or death had occurred in 12 patients in the ibrutinib-venetoclax group and 75 patients in the FCR group. A total of nine deaths occurred in the ibrutinib-venetoclax group and 25 in the FCR group.
Over half of the patients in the ibrutinib-venetoclax group had stopped therapy due to undetectable MRD at three years. After five years of ibrutinib-venetoclax treatment, 65.9 per cent of the patients had undetectable MRD in the bone marrow and 92.7 per cent had undetectable MRD in peripheral blood.
Safety profiles showed comparable risks for infections in both groups; however, more patients experienced severe cardiac adverse events in the ibrutinib-venetoclax group (10.7 per cent vs 0.4 per cent).
A total of 24 secondary cancers were diagnosed in 17 patients in the ibrutinib-venetoclax group and 45 secondary cancers were diagnosed in 34 patients that received FCR, who were approximately eight times as likely to have disease progression compared with patients who received ibrutinib-venetoclax therapy. This was consistent regardless of gender, age, or disease stage, even in patients with a poor prognosis.
“This is the first time this combination treatment has shown overall survival compared to standard treatment,” according to Prof Hillmen.
Primary analysis of the multinational randomised, double-blind, phase 3 SYMPATICO trial was also presented at ASH 2023. The trial compared the efficacy and safety of combining ibrutinib and venetoclax with ibrutinib and placebo in patients with relapsed or refractory mantle cell lymphoma (MCL).
The sample population consisted of 267 adults with MCL who had received one-to-five previous lines of therapy, including at least one regimen with anti-CD20 therapy. This analysis found a statistically significant improvement in progression-free survival among those in the ibrutinib and venetoclax group, and also supports the combinational therapy.
Coping strategies used prior to haematopoietic cell transplantation significantly influence quality-of-life and psychological distress
Supportive care interventions to promote approach-oriented coping strategies are required to optimise quality-of-life and reduce psychological distress during and prior to haematopoietic cell transplantation (HCT), according to data presented at the AmericanSociety of Haematology Annual Meeting 2023.
Avoidant coping strategies were significantly associated with higher levels of psychological distress among adults with haematologic cancers undergoing HCT at three tertiary care academic centres. Key sociodemographic factors including age, gender, income level, and employment status were associated with avoidant coping utilisation.
Dr Richard Newcomb, Harvard Medical School, Boston, who led the study, presented findings from the secondary analysis of baseline data from a multi-site randomised controlled trial that evaluated a supportive care intervention for patients with haematologic malignancies undergoing allogeneic or autologous HCT.
In the study, researchers assessed quality-of-life, psychological distress, and coping strategies within 72 hours of admission for HCT, using the median split method to dichotomise coping, and multivariate regression analyses to characterise the association of coping with psychological distress and quality-of-life. The investigation was carried out to fill the deficit in available literature in on coping during HCT.
Results showed that 31.3 per cent of patients were high utilisers of avoidant coping, 43.5 per cent were high utilisers of approach-oriented coping, and notably, 11.9 per cent of patients identified as high utilisers of both approach-oriented and avoidant coping.
No sociodemographic or clinical factors were associated with use of approach-oriented coping, while older age and higher income were associated with less frequent use of avoidant coping. Female gender and disabled employment status were associated with increased likelihood of high avoidant coping use.
High use of approach-oriented coping was associated with better pre-HCT quality-of-life and lower depression and anxiety symptoms. High use of avoidant coping was associated with worse pre-HCT quality-of-life and symptoms of depression, anxiety, and post-traumatic stress disorder.
Geriatric assessment tools predict chemotherapy toxicity
A prospective study presented at the AmericanSociety of Haematology Annual Meeting 2023 that investigated the use of geriatric assessment tools to identify patients with non-Hodgkin lymphoma (NHL) that will suffer treatment toxicities found that several simple interventions can predict which patients will experience negative outcomes.
Lead investigator Dr Pallawi Torka, Memorial Sloan Kettering Cancer Centre, New Jersey, US told attendees “the time is right for incorporating geriatric assessment into practice”.
NHL represents 43 per cent of all blood cancers in Ireland, and almost a third of patients are over 65 years. Older patients have significantly worse relapse-free and overall survival than younger sufferers, and treatment toxicity is also more common in older adults. Patients who experience toxic effects generally derive less benefit from treatment regimes.
A total of 194 pts with confirmed diagnoses of NHL starting a new chemotherapy regimen were included in the study. Most of the patients had diffuse large B-cell lymphoma (DLBCL), and 75 per cent had been diagnosed with advanced disease.
Geriatric assessment was performed prior to pre-phase therapy in those who received it; prior to initiation of the new chemo; within seven days prior to each cycle (up to six); and one month (+/- 10 days) after completion of treatment.
Assessment tools included patients’ self-reported Karnofsky Performance Scale(KPS) index, the Activities of Daily Living (ADL) subscale of the Medical Outcomes Survey (MOS), the Instrumental Activities of Daily Living (IADL) subscale of the Older Americans Resources and Services (OARS) instrument, number of falls in the past six months, the Mini Nutritional Assessment (MNA) for nutrition and polypharmacy, and the ‘Timed Up and Go (TUG) test’. Comorbidity, cognition, and social support were also assessed.
Several components of the geriatric assessment, particularly low ADL score, self-reported KPS, and abnormal TUG, were associated with severe treatment-related toxicity in older patients with NHL receiving systemic chemotherapy, Dr Torka said, and advocated the utilisation of the TUG test in particular.
The simple assessment uses the time a patient takes to rise from a chair, walk three metres, turn around, walk back to the chair, and sit back down. TUG is usually utilised to determine mobility and falls risk in older patients. Dr Torka and colleagues concluded by calling for the simple test to be “incorporated in treatment decision making” for older patients with NHL.
Gene therapy shows promising results in sickle cell disease
Trial updates for two new products, lovotibeglogene autotemcel (lovo-cel) and exagamglogene autotemcel (exa-cel), both of which were recently approved by the Food and Drug Administration (FDA) in December 2023, indicate that gene therapies may “provide a one-time functional cure to patients with sickle cell disease (SCD)”, according to Dr Haydar Frangoul, Children’s Hospital at TriStar Centennial, Nashville, Tennessee, US.
Dr Frangoul was one of several speakers that presented profoundly positive data from ongoing investigations into the efficacy and safety gene therapy in SCD at the AmericanSociety of Haematology Annual Meeting 2023.
Exa-cel is a non-viral cell therapy designed to reactivate foetal haemoglobin via ex vivo CRISPR-Cas9 gene-editing of autologous CD34+ HSPCs at the erythroid-specific enhancer region of the BCL11A gene.
Dr Frangoul delivered an overview of findings from an interim analysis of CLIMB SCD-121, an ongoing phase 3 trial of exa-cel in patients aged between 12-to-35 with SCD. Participants in the trial experienced “rapid, robust, and durable” improvements in total haemoglobin, and all other endpoints were met after myeloablative conditioning followed by a one-time infusion of exa-cel, Dr Frangoul said.
Of the evaluable patients receiving the CRISPR-Cas9 gene editing therapy, 95 per cent remained free from vaso-occlusive events (VOEs) at 12 months and after. Participants also showed significant improvements in quality-of-life.
Similarly positive data were presented in support of lovo-cel gene therapy, which uses autologous transplantation of HSPCs transduced with the BB305 lentiviral vector encoding a modified β-globin gene that produces an anti-sickling haemoglobin.
An analysis of the phase 1/2 HGB-206 and phase 3 HGB-210 studies of lovo-cel, which are the largest clinical trials of gene therapy in SCD to date, showed that 90.9 per cent of evaluable participants experienced complete resolution of VOEs. Health-related quality-of-life, pain intensity and interference, and fatigue also improved. Adverse events were reportedly similar to known side-effects of myeloablative conditioning.
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