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.

BEAM-Campath Allogeneic Stem Cell Transplant for Patients with Relapsed/Refractory Lymphoma: High Incidence of Long-Term Mixed Donor-Recipient Chimerism and the Response to Donor Lymphocyte Infusions.

BiCNU (carmustine), etoposide, Ara-C, melphalan (BEAM) and Campath conditioning was developed to reduce the high transplant-related mortality in patients with lymphoma while delivering intensive antilymphoma immunotherapy, as well as to some extent a platform for allogeneic stem cell engraftment. Significant numbers of patients appeared to have persistent recipient-derived hematopoiesis, and therefore we retrospectively analyzed patients with lymphoma undergoing BEAM-Campath conditioned allogeneic stem cell transplantation at our center (2003 to 2017) to characterize the patterns of chimerism and patient outcomes. Chimerism was analyzed with short tandem repeat PCR. Mixed donor-recipient chimerism (MDRC) was defined as 5% to 94.9% donor. Fifty-two patients (n = 30 male), with a median age of 45 years, were identified with histologic diagnoses of Hodgkin lymphoma (n = 13), diffuse large B cell lymphoma (n = 7), low-grade non-Hodgkin lymphoma (n = 16), mantle cell lymphoma (n = 10), and T cell lymphoma (n = 6). Pretransplant, 93% achieved complete response (52%) or partial response (41%) with a median of 3 prior therapies (n = 3 prior autologous stem cell transplantation). Donors were Matched sibling donors (MSD) (n = 21), matched unrelated donors (MUD) (n = 24), miss-matched unrelated donors (MMUD) (n = 6), and syngeneic (n = 1). Acute graft-versus host disease (GVHD) developed in 52% (81% grade I to II) and chronic GVHD (83% extensive) in 12%. MDRC of T cells (MDRCt) developed in 62% (n = 32), and 29% (n = 15) developed MDRC of myeloid cells (MDRCm) at a median onset of 100 days. Donor lymphocyte infusion (DLI) was given to 17 patients, with a median starting dose of 1 × 106/kg. The first DLI was given at a median of 225 days post-transplant (range, 99 days to 5.3 years). Of these, 9 developed acute post-DLI GVHD and 2 limited chronic GVHD. Conversion to full donor occurred in 47% MDRCt and 50% MDRCm. Multivariate analysis identified sibling donor type as associated with increased MDRCt (P = .035; hazard ratio [HR], 0.17) and reduced total nucleated cell dose with increased MDRCm (P = .021; HR, 0.76). The median follow-up was 6 years, and 2-year NRM cumulative incidence was 16% (95% confidence interval [CI], 7% to 27%). Ten-year progression and extensive GVHD-free survival was 45% (95% CI, 28% to 61%), and overall survival was 66% (95% CI, 50% to 78%). One-year landmark analysis identified no increased GVHD or relapse risk with MDRCt or MDRCm but reduced nonrelapse mortality (NRM) risk with MDRCt (P = .001). BEAM-Campath allografts for high-risk lymphoma achieve long-term disease-free survival with low rates of GVHD and transplant-related mortality. The frequent development of myeloid MDRC demonstrates that BEAM-Campath is a nonmyeloablative conditioning regimen in almost a third of patients. MDRCt is associated with reduced NRM, but neither MDRCt or MDRCm is associated with increased GVHD or relapse.

Do patients die well in your emergency department?

OBJECTIVES: Although the role of the ED in the management of patients needing palliative care is recognised internationally, there are little Australasian data on this issue. This study aimed to determine the current knowledge and attitude to the provision of palliative care in Australasian EDs. METHODS: All ED directors in Australasia were invited to complete an online survey about the provision of palliative care in their department. Quantitative data were described using counts and proportions, and qualitative data were summarised thematically. RESULTS: Of 165 eligible ED directors, 35 completed the survey (22%; 95% CI, 15-28%). Only 17/35 (49%; 95% CI, 32-65%) believed that ED provided good palliative care, and 28/35 (80%; 95% CI, 67-93%) were unaware of international gold standard palliative care protocols. Most had access to hospital-based palliative care specialists 27/35 (77%; 95% CI, 63-91%); however, only 5/27 (19%; 95% CI, 4-33%) used them. Few EDs undertake formal training in palliative care 10/35 (29%; 95% CI, 16-45%). Respondents showed concern about the quality of palliative care they provide and advocated for more palliative care training. CONCLUSION: Although limited by the low response rate, this survey indicates that there is a need and a desire for greater integration of the values and standards of high-quality palliative care in Australasian EDs.

The prognostic significance of steroid receptor co-regulators in breast cancer: co-repressor NCOR2/SMRT is an independent indicator of poor outcome.

BACKGROUND: Advances in understanding the molecular basis of breast cancer has necessitated a definition of improved indicators of prognosis that are central to the underlying cancer biology and that reflect the heterogeneous nature of the disease. This study investigates the pattern of expression of the steroid receptor co-regulators NCOA1/SRC1, NCOA3/RAC3, NCOR2/SMRT, and CBP/p300 in breast cancer. The aims were to identify whether their expression was related to patient outcome, their relationships to known prognostic factors and to provide a basis for further research into the mechanistic significance of such associations. METHODS: The protein levels of steroid receptor co-regulators were assessed by immunohistochemistry in a large well-characterised series of breast carcinomas prepared as tissue microarrays. Relationships between these targets, other clinicopathological variables and patients' outcome were examined. RESULTS: NCOR2/SMRT was an independent prognostic indicator of overall patient survival (OS) and disease free interval (DFI) and was significantly correlated with distant metastases and local recurrence whereas tumours expressing NCOA1/SRC1 had a significantly longer OS and DFI. There were also significant correlations between co-regulator expression of NCOA1/SRC1, CBP/p300 and NCOA3/RAC3, which were associated with lower tumour grade. NCOA1/SRC1 was also correlated with smaller tumour size. Furthermore, the co-activators had a significant association with steroid receptors, particularly ERalpha. CONCLUSIONS: NCOR2/SMRT is associated with poor patient outcome, independent of other prognostic factors. In contrast, steroid receptor co-activator expression is generally associated with a good prognosis. Further investigations are needed to establish the mechanisms of these links between the steroid receptor co-regulator system and patient outcome.

Synthesis and properties of [NiCp*(2,5-tBu2PC4H2)], a 20-valence-electron phosphanickelocene.

The reaction of the bulky phospholide salt Li(2,5-tBu2PC4H2) x 2THF (1; THF = tetrahydrofuran) with [NiCp*(acac)] (HCp* = pentamethylcyclopentadiene, Hacac = acetylacetone) gives the green air-sensitive phosphanickelocene [NiCp*(2,5-tBu2PC4H2)] (2) in yields of about 85%. An X-ray structural determination of 2 shows long Ni-ring bonds and "delocalised" ring P-C and C-C bonds characteristic of a classical 20-valence-electron (ve) nickelocene. The electronic structure of 2 has been clarified through a combined Amsterdam density functional (ADF) and photoelectron spectroscopic study, which indicates that the higher lying semi-occupied molecular orbital (SOMO) (-5.82 eV) has a' symmetry and that the phosphorus "lone pair" is energetically low-lying (-8.15 eV). Oxidation of phosphanickelocene 2 by AgBF4 occurs quantitatively to give the corresponding air-sensitive orange phosphanickelocenium salt [NiCp*(2,5-tBu2PC4H2)][BF4] (3). This complex has also been characterised by an X-ray crystallographic study, which reveals long Ni-C(alpha) and short C(alpha)-C(beta) bonds in the phospholyl ligand indicative of a SOMO having a'' symmetry. PMe3 reacts with 2 at room temperature to provoke a ring-slip reaction that gives the 18ve complex [NiCp*eta1-(2,5-tBu2PC4H2)(PMe3)] (4), but shows no reaction with the phosphanickelocenium salt 3 under the same conditions.

Synthesis and properties of [CoCp*(2,5-PC4tBu2H2)]: the first monophosphacobaltocene.

The reduction of the phosphacobaltocenium salt [CoCp*(2,5-PC(4)tBu(2)H(2))](+)[BPh(4)](-) (3; Cp*=pentamethylcyclopentadienyl) by magnesium in tetrahydrofuran (THF) furnishes the stable air-sensitive phosphacobaltocene [CoCp*(2,5-PC(4)tBu(2)H(2))] (4) in yields of up to 80 %. The crystal structure of 4 shows long Co-C(alpha) and short C(alpha)-C(beta)bonds in the phospholyl ligand, consistent with a semi-occupied molecular orbital (SOMO) having a" symmetry. A combined Amsterdam density functional (ADF)/photoelectron spectroscopic study, which confirms this assignment, gives ionisation energies (IE) of 5.02 eV from the SOMO and 8.89 eV from the phosphorus "lone pair". A comparison of cyclovoltammograms for 3 and the corresponding cyclopentadienyl complex [CoCp*(1,3-C(5)tBu(2)H(3))](+) [BPh(4)](-)(5) shows that replacing a CH group by an sp(2) phosphorus atom results in an anodic first reduction potential shift of 0.29 V.