Ibrutinib as part of risk-stratified treatment for post-transplant lymphoproliferative disorder: The phase 2 TIDaL trial.

Post-transplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation, and cytotoxic chemotherapy is associated with treatment-related morbidity and mortality. Current treatment takes a sequential, risk-stratified approach, patients with low-risk disease following initial immunotherapy can avoid escalation to immunochemotherapy. TIDaL is a prospective, single-arm phase 2 trial investigating the activity and tolerability of ibrutinib combined with risk-stratified therapy for first-line treatment of PTLD. Eligible patients were adults with newly-diagnosed CD20-positive B-cell PTLD after solid organ transplant and performance status 0 to 2. Initial treatment comprised 49 days of ibrutinib 560mg once daily, with 4 doses of weekly rituximab. Treatment response on interim scan and baseline international prognostic index were used to allocate patients to either a low-risk arm (who continued ibrutinib, alongside 4 further doses of 3-weekly rituximab) or high-risk (escalation to R-CHOP immunochemotherapy, ibrutinib continuing in patients aged <65 years). The primary outcome was complete response on interim scan, achieved by 11/38 patients (29%, 95% confidence interval (CI) 15% - 46%). This did not reach the pre-specified threshold for clinically significant activity. Secondary outcomes included allocation to the low-risk arm (41% of patients), 2-year progression-free survival (58%, 95% CI 44% - 76%), and 2-year overall survival (76%, 95% CI 63% - 91%). Adverse events were mostly haematological, gastrointestinal and infective. Whilst TIDaL does not support adding ibrutinib into first-line treatment of PTLD, increasing the proportion of patients who can be treated without cytotoxic chemotherapy remains an important aim of future research. This trial was registered as ISRCTN32667607.

Ibrutinib as first-line therapy for mantle cell lymphoma: a multicenter, real-world UK study.

ABSTRACT: During the COVID-19 pandemic, ibrutinib with or without rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. Because limited data are available in this setting, we conducted an observational cohort study evaluating safety and efficacy. Adults receiving ibrutinib with or without rituximab for untreated MCL were evaluated for treatment toxicity, response, and survival, including outcomes in high-risk MCL (TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 ≥ 30%). A total of 149 patients from 43 participating centers were enrolled: 74.1% male, median age 75 years, 75.2% Eastern Cooperative Oncology Group status of 0 to 1, 36.2% high-risk, and 8.9% autologous transplant candidates. All patients received ≥1 cycle ibrutinib (median, 8 cycles), 39.0% with rituximab. Grade ≥3 toxicity occurred in 20.3%, and 33.8% required dose reductions/delays. At 15.6-month median follow-up, 41.6% discontinued ibrutinib, 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2%, respectively. ORR was 77.3% (low risk) vs 59.0% (high risk) (P = .05) and 78.7% (ibrutinib-rituximab) vs 64.9% (ibrutinib; P = .13). Median progression-free survival (PFS) was 26.0 months (all patients); 13.7 months (high risk) vs not reached (NR) (low risk; hazard ratio [HR], 2.19; P = .004). Median overall survival was NR (all); 14.8 months (high risk) vs NR (low risk; HR, 2.36; P = .005). Median post-ibrutinib survival was 1.4 months, longer in 41.9% patients receiving subsequent treatment (median, 8.6 vs 0.6 months; HR, 0.36; P = .002). Ibrutinib with or without rituximab was effective and well tolerated as first-line treatment of MCL, including older and transplant-ineligible patients. PFS and OS were significantly inferior in one-third of patients with high-risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups.

Non-Responsive and Refractory Coeliac Disease: Experience from the NHS England National Centre.

We characterised the aetiology of non-responsive coeliac disease (NRCD) and provided contemporary mortality data in refractory coeliac disease (RCD) from our centre. We also measured urine gluten immunogenic peptides (GIPs) in patients with established RCD1 to evaluate gluten exposure in these individuals. METHODS: This was a longitudinal cohort study conducted in Sheffield, UK. Between 1998 and 2019, we evaluated 285 adult (≥16 years) patients with NRCD or RCD. Patients with established RCD1 and persisting mucosal inflammation and/or ongoing symptoms provided three urine samples for GIP analysis. RESULTS: The most common cause of NRCD across the cohort was gluten exposure (72/285; 25.3%). RCD accounted for 65/285 patients (22.8%), 54/65 patients (83.1%) had RCD1 and 11/65 patients (16.9%) had RCD2. The estimated 5-year survival was 90% for RCD1 and 58% for RCD2 (p = 0.016). A total of 36/54 (66.7%) patients with RCD1 underwent urinary GIP testing and 17/36 (47.2%) had at least one positive urinary GIP test. CONCLUSION: The contemporary mortality data in RCD2 remains poor; patients with suspected RCD2 should be referred to a recognised national centre for consideration of novel therapies. The high frequency of urinary GIP positivity suggests that gluten exposure may be common in RCD1; further studies with matched controls are warranted to assess this further.

A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial.

Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. A 3 + 3 design investigated the recommended phase 2 dose of thiotepa for a single-stage phase 2 cohort by assessing the activity of 2 cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated that 50 mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase 1, and TIER was well-tolerated by the 27 patients treated in phase 2. The most common grade 3 to 4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 patients (52%), which met the prespecified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval [CI], 2 to 6 months) and overall survival 5 months (95% CI, 3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplantation (ASCT) consolidation, with 4 experiencing durable remissions after a median follow-up of 50 months. The TIER regimen can be delivered safely and is active against rrPCNSL. When it is followed by ASCT, it can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor, and novel treatment strategies are urgently needed. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/search as EudraCT 2014-000227-24 and ISRCTN 12857473.

Long-term survivors following autologous haematopoetic stem cell transplantation have significant defects in their humoral immunity against vaccine preventable diseases, years on from transplant.

Current international guidelines recommend routinely vaccinating haematopoetic stem cell transplant (HSCT) recipients. Despite significant infection-related mortality following autologous HSCT, routine vaccination programmes (RVP) completion is poor. For recovered HSCT recipients, it is uncertain whether catch-up vaccination remains worthwhile years later. To determine potential susceptibility to vaccine preventable infections, we measured antibody titres in 56 patients, a median of 7 years (range 0-29) following autologous HSCT, who had not completed RVP. We found that almost all participants had inadequate titres against diphtheria (98.2%) and pneumococcal infection (100%), and a significant proportion had inadequate titres against measles (34.5%). Of those subsequently vaccinated according to available guidelines, many mounted adequate serological responses. These data suggest a pragmatic catch-up approach for autologous HSCT recipients who have not completed RVP is advisable, with universal vaccination against some pathogens (e.g. Streptococcus pneumoniae and diphtheria) and serologically-guided approaches for others (e.g. measles and varicella zoster virus).

Real-world Outcomes With Rituximab-based Therapy for Posttransplant Lymphoproliferative Disease Arising After Solid Organ Transplant.

BACKGROUND: Optimal upfront therapy for posttransplant lymphoproliferative disease (PTLD) arising after solid organ transplant remains contentious. Rituximab monotherapy (R-Mono) in unselected patients has shown a lack of durable remissions. Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-based chemotherapy confers improved response rates, although concerns exist about toxicity. METHODS: This multicenter retrospective study reports outcomes for adults with biopsy-proven B-cell PTLD treated initially with R-Mono or Rituximab plus CHOP (R-CHOP). Selection of therapy was made according to physician preference. RESULTS: Among 101 patients, 41 received R-Mono and 60 had R-CHOP. Most (93%) had undergone renal or liver transplantation. R-CHOP showed a trend toward improved complete (53% versus 71%; P = 0.066) and overall (75% versus 90%; P = 0.054) response rates. In the R-Mono group, 13 of 41 (32%) subsequently received chemotherapy, while 25 of 41 (61%) remained progression-free without further therapy. With median follow-up of 47 months, overall survival (OS) was similar for R-Mono and R-CHOP, with 3-year OS of 71% and 63%, respectively (P = 0.722). Non-PTLD mortality was 3 of 41 (7%) and 4 of 60 (7%) within 12 months of R-Mono or R-CHOP, respectively. The International Prognostic Index was statistically significant, with low- (0-2 points) and high-risk (≥3 points) groups exhibiting 3-year OS of 78% and 54%, respectively (P = 0.0003). In low-risk PTLD, outcomes were similar between therapies. However, in high-risk disease R-Mono conferred an inferior complete response rate (21% versus 68%; P = 0.006), albeit with no impact on survival. CONCLUSIONS: Our data support R-Mono as initial therapy for PTLD arising after renal or liver transplantation. However, upfront R-CHOP may benefit selected high-risk cases in whom rapid attainment of response is desirable.

Protecting vulnerable patients with inherited anaemias from unnecessary death during the COVID-19 pandemic.

With the developing COVID-19 pandemic, patients with inherited anaemias require specific advice regarding isolation and changes to usual treatment schedules. The National Haemoglobinopathy Panel (NHP) has issued guidance on the care of patients with sickle cell disease, thalassaemia, Diamond Blackfan anaemia (DBA), congenital dyserythropoietic anaemia (CDA), sideroblastic anaemia, pyruvate kinase deficiency and other red cell enzyme and membrane disorders. Cascading of accurate information for clinicians and patients is paramount to preventing adverse outcomes, such as patients who are at increased risk of fulminant bacterial infection due to their condition or its treatment erroneously self-isolating if their fever is mistakenly attributed to a viral cause, delaying potentially life-saving antibiotic therapy. Outpatient visits should be minimised for most patients, however some, such as first transcranial dopplers for children with sickle cell anaemia should not be delayed as known risk of stroke will outweigh the unknown risk from COVID-19 infection. Blood transfusion programmes should be continued, but specific changes to usual clinical pathways can be instituted to reduce risk of patient exposure to COVID-19, as well as contingency planning for possible reductions in blood available for transfusions. Bone marrow transplants for these disorders should be postponed until further notice. With the current lack of evidence on the risk and complications of COVID-19 infection in these patients, national data collection is ongoing to record outcomes and eventually to identify predictors of disease severity, particularly important if further waves of infection travel through the population.

Outcomes of older patients with primary central nervous system lymphoma treated in routine clinical practice in the UK: methotrexate dose intensity correlates with response and survival.

Data on older patients with primary central nervous system lymphoma (PCNSL) are scarce. Comorbidities and performance status frequently compromise outcomes in this group. Medical records for consecutive patients ≥65 years (n = 244) with PCNSL diagnosed 2012-2017 from 14 UK centres were retrospectively reviewed. Of these 192 patients received methotrexate (MTX)-based treatment. Patients were categorised based on clinician's treatment choice into 'palliative' (n = 52), 'less intensive: MTX ± rituximab ± alkylators' (n = 74) and 'intensive: MTX/cytarabine combinations' (n = 118) groups. Complete remission (CR) rate, two-year progression-free survival (PFS) and overall survival (OS) rates were 49%, 11% and 24% for the less intensive and 69%, 40% and 50% for the intensive groups. Treatment-related mortality (TRM) was 6·8% for MTX-treated patients. Median MTX cumulative dose was 8·8 g/m2 (range 1·5-21) over a median of three cycles. Higher relative dose intensity of MTX (MTX-RDI) was associated with improved PFS and OS in both groups adjusting for age, Eastern cooperative oncology group (ECOG) score and baseline parameters. Two-year PFS and OS for patients receiving four or more induction cycles followed by consolidation (n = 36) were 65% and 70% respectively. Older patients completing MTX-based induction and consolidation had clinical outcomes similar to those in younger cohorts. These retrospective data suggest that maximising MTX-RDI and delivering consolidation in a subgroup of older patients may improve clinical outcomes.

Ibrutinib for Treating Waldenström's Macroglobulinaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its Single Technology Appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer of ibrutinib (Janssen) to submit evidence on the clinical and cost effectiveness of ibrutinib for treating Waldenström's macroglobulinaemia (WM). The School of Health and Related Research Technology Assessment Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of ibrutinib based on the company's submission to NICE. The clinical evidence was derived from one phase II, single-arm, open-label study of ibrutinib in adult patients with WM who had received at least one prior therapy (Study 1118E) and an indirect comparison using a matched cohort from a retrospective European chart review of patients receiving various treatments for WM. The indirect comparison suggested a hazard ratio for progression-free survival (PFS) of 0.25 (95% confidence interval 0.11-0.57). The ERG had concerns regarding the high risk of bias in Study 1118E, the limited generalisability of the study, and the absence of randomised controlled trial evidence. The company's Markov model assessed the cost effectiveness of ibrutinib versus rituximab/chemotherapy for patients with relapsed/refractory (R/R) WM from the perspective of the National Health Service (NHS) and Personal Social Services (PSS) over a lifetime horizon. Based on the company's original Patient Access Scheme (PAS), the company's probabilistic model generated an incremental cost-effectiveness ratio (ICER) for ibrutinib versus rituximab/chemotherapy of £58,905 per quality-adjusted life-year (QALY) gained. Following a critique of the model, the ERG's preferred analysis, which corrected cost errors and used the observed mortality rate from Study 1118E, generated a probabilistic ICER of £61,219 per QALY gained. Based on this amended model, additional exploratory analyses produced ICERs for ibrutinib that were > £60,000 per QALY gained. Subsequently, the company offered to provide ibrutinib at a price that resulted in ibrutinib being cost effective within the Cancer Drugs Fund (CDF). The Committee recommended ibrutinib for use in the CDF as an option for treating WM in adults who have had at least one prior therapy, only if the conditions in the managed access agreement for ibrutinib are followed.

The management of painful crisis in sickle cell disease.

PURPOSE OF REVIEW: Until recently management of sickle pain was the province of haematologists. However, a recent National Confidential Enquiry into Patient Outcome and Death report highlighted problems with the management of pain and opioid analgesia in this group and suggested a multiagency approach similar to that used in palliative care. RECENT FINDINGS: Pain is the most frequent complication of this haemoglobin disorder. Sickle cell disease is very variable with many patients leading full lives with long periods with little or no pain. At the other end of the spectrum there are those who exist in a sea of pain. The mechanisms of sickle pain are poorly understood and evidence for the best treatment modalities sparse. Historically there has been a dearth of clinical trials in sickle cell; however, this is starting to be addressed. SUMMARY: In this review we will give a brief overview of the disease and its pathogenesis before examining the epidemiology, management of pain in sickle cell disease. We will also review recent evidence regarding quality of life and discuss the role of opioid hyperalgesia in sickle cell disease.

Plasma levels of tissue factor and soluble E-selectin in sickle cell disease: relationship to genotype and to inflammation.

BACKGROUND: Microvascular occlusion, the pathophysiological hallmark of sickle cell disease (SCD), is a complex multifactorial process with alterations in coagulation, endothelial function and inflammation. However, relationships between these process in the two most common genotypes, HbSS and HbSC, are unknown. We hypothesized differences in the hypercoagulable state [as assessed by tissue factor (TF), fibrinogen and D-dimer], endothelial function [markers soluble E-selectin (sE-sel) and von Willebrand factor (vWf)], and inflammation [markers interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP)] in these two SCD genotypes. Citrated plasma TF, sE-sel, vWf, fibrinogen and fibrin D-dimer, and serum IL-6 and hsCRP (enzyme-linked immunosorbent assay/Clauss) were measured in 64 patients with SCD (27 with HbSS disease) and 42 AA subjects matched for age and ethnic origin. TF (P = 0.0014), sE-sel (P = 0.001) and, as expected, vWf, D-dimer, and hsCRP (all P < or = 0.01), but not fibrinogen or IL-6, were raised in the SCD patients compared with the AA subjects. However, only vWf and, as expected, D-dimer (all P < or = 0.01) were higher in HbSS disease than in HbSC disease. Raised plasma TF and sE-sel in SCD compared with HbAA subjects may contribute to the increased risk of thrombotic disease in this group. Raised vWf in HbSS compared with HbSC may be important in determining pathophysiology in these two genotypes. Positive correlations between IL-6 and TF in both HbSC and HbSS disease leads us to speculate that inflammation may be important in coagulation activation in these patients, or vice versa. However, lack of correlation of sE-sel with inflammatory markers implies that other mechanisms are responsible for increased levels of this marker of endothelial activation.

Platelet activation and endothelial cell dysfunction in sickle cell disease is unrelated to reduced antioxidant capacity.

Possible pathogenetic processes in sickle cell disease include antioxidants, endothelial and platelet changes, and hypercoagulability. Hypothesizing relationships between these processes, we recruited 47 young adult patients (mean age 19 years) with homozygous sickle cell disease and 40 age-, race- and sex-matched healthy controls and measured plasma markers representative of these processes. We found raised plasma von Willebrand factor (P = 0.001) and intercellular adhesion molecule (P = 0.016, both marking endothelial perturbation, but the latter also marking inflammation), raised soluble P selectin (P = 0.002) (marking platelet activation) and inflammation marker C reactive protein (P = 0.021), but reduced antioxidant capacity (P = 0.002) in patients compared with controls. There was no difference in fibrinogen and there was no significant correlation between any of the indices. Our data suggest that changes in endothelial and platelet function in sickle cell disease are unrelated to reduced antioxidant capacity.