Day-21 bone marrow findings incorrectly designate residual leukaemia in FLT3-mutated acute myeloid leukaemia treated with intensive induction plus midostaurin: a morphology-focused study.

Early induction response assessment with day-21 bone marrow (D21-BM) is commonly performed in patients with FLT3-mutated acute myeloid leukaemia (AML), where detection of residual leukaemia (RL; blasts ≥5%) typically results in the administration of a second induction course. However, whether D21-BM results predict for RL at the end of first induction has not been systematically assessed. This study evaluates the predictive role of D21-BM morphology in detecting RL following first induction. Between August 2018 and March 2022, all patients with FLT3-AML receiving 7+3 plus midostaurin, with D21-BM performed, were identified. Correlation between D21-BM morphology vs D21-BM ancillary flow/molecular results, as well as vs D28-BM end of first induction response, were retrospectively reviewed. Subsequently, D21-BMs were subjected to anonymised morphological re-assessments by independent haematopathologists (total in triplicate per patient). Of nine patients included in this study, three (33%) were designated to have RL at D21-BM, all of whom entered complete remission at D28-BM. Furthermore, only low-level measurable residual disease was detected in all three cases by flow or molecular methods at D21-BM, hence none proceeded to a second induction. Independent re-evaluations of these cases failed to correctly reassign D21-BM responses, yielding a final false positive rate of 33%. In summary, based on morphology alone, D21-BM assessment following 7+3 intensive induction plus midostaurin for FLT3-AML incorrectly designates RL in some patients; thus correlating with associated flow and molecular results is essential before concluding RL following first induction. Where remission status is unclear, repeat D28-BMs should be performed.

Rationally designed chimeric PI3K-BET bromodomain inhibitors elicit curative responses in MYC-driven lymphoma.

Targeted inhibitors of bromodomain and extraterminal (BET)-bromodomains and phosphatidylinositol-3-kinase (PI3K) signaling demonstrate potent but self-limited antilymphoma activity as single agents in the context of cellular Myelocytomatosis (cMYC) oncogene-dysregulation. However, combined PI3K and BET inhibition imparts synergistic anticancer activity with the potential for more sustained disease responses due to the mutual antagonism of compensatory epigenetic and signaling networks. Here, we describe the mechanistic and therapeutic validation of rationally designed dual PI3K/BET bromodomain inhibitors, built by linkage of established PI3K and BET inhibitor pharmacophores. The lead candidate demonstrates high selectivity, nanomolar range cellular potency, and compelling in vivo efficacy, including curative responses in the aggressive Eµ-Myc lymphoma model. These studies further support the therapeutic strategy of combined PI3K and BET inhibition and provide a potential step-change in approach to orthogonal MYC antagonism using optimized chimeric small-molecule technology.

Ischaemic stroke and transient ischaemic attack on anticoagulants: outcomes in the era of direct oral anticoagulants.

Clinical and imaging characteristics of patients receiving direct oral anticoagulants presenting with transient ischaemic attack or stroke are lacking. A retrospective review of all patients who presented to a high-volume primary stroke centre with acute stroke symptoms while prescribed an oral anticoagulant between January 2012 and June 2017. Clinical, radiological characteristics and functional outcomes were examined. Anticoagulated patients diagnosed with stroke or transient ischaemic attack shared similar disease and outcome characteristics irrespective of anticoagulants used. One-third of warfarin patients with sub-therapeutic international normalised ratios were treated with thrombolytics but no direct oral anticoagulants level was performed in any of the patients, with only one treated by intravenous thrombolysis.

Autologous transplantation improves survival rates for follicular lymphoma patients who relapse within two years of chemoimmunotherapy: a multi-center retrospective analysis of consecutively treated patients in the real world.

Although chemoimmunotherapy improves outcomes for patients with follicular lymphoma (FL), approximately 20% of patients experience early disease progression within two years of treatment and subsequently poor median survival. We conducted a retrospective study to evaluate survival rates of patients with early relapse who were treated with or without autologous transplantation. Of 517 patients with FL and who received chemoimmunotherapy, 152 relapsed and survived a minimum of four months after progression, including 84 (55.3%) with early relapse ≤2 years following initial therapy and 68 (44.7%) with later relapse. Five-year survival was superior for patients who received autologous transplantation compared to non-transplanted patients within the early relapse group (85.4% vs 57.9%, p = .001), but not within the late relapse group (p = .64). Given the limitations of a retrospective study, our study may suggest that the use of autologous transplantation for FL patients who relapse within two years of initial chemoimmunotherapy is associated with improved survival.

The Adverse Consequences of Initial Watchful Waiting for Patients With Follicular Lymphoma.

BACKGROUND: Patients with low tumor burden follicular lymphoma (FL) are commonly managed with watchful waiting (WW). The incidence of organ dysfunction and/or transformation at disease progression, and subsequent impact on outcomes is poorly understood. PATIENTS AND METHODS: Patients managed with WW during 1994 to 2011 were identified through the Alberta Lymphoma Database. Individuals receiving immediate rituximab (R)-chemotherapy were identified as a comparator group to those on WW who received R-chemotherapy at progression. Endpoints included transformation, organ dysfunction, time to progression, time to next treatment, progression-free survival (PFS) after chemotherapy, and overall survival (OS). RESULTS: We identified 238 patients managed with WW (28.9% of registry patients) during this 17-year period. The median follow up was 8.2 years. At a median of 29.9 months, 58 (24.4%) of these patients developed organ dysfunction and/or transformation. Of 169 (71%) patients who required therapy, 10-year OS was inferior for those with transformation (hazard ratio, 2.88; P = .002) and organ dysfunction (hazard ratio, 2.10; P = .028). PFS after R-chemotherapy and OS in patients without organ dysfunction and/or transformation was not affected by the initial WW period, compared with immediate R-chemotherapy. WW resulted in increased high risk FL International Prognostic Index scores at initiation of R-chemotherapy (45% vs. 20%), and more frequent transformation at progression (5-year risk, 17.8% vs. 3.5%; P < .001). Baseline characteristics did not predict organ dysfunction. CONCLUSION: Patients with FL accepting initial WW should be aware of the 1 in 4 risk of organ dysfunction and/or transformation, and subsequent inferior OS. Physicians should consider surveillance for progression to consider early therapy.

Urolithiasis is prevalent and associated with reduced bone mineral density in ß-thalassaemia major.

Asymptomatic urolithiasis is common and of mixed composition in patients with ß-thalassaemia major. Twenty-seven subjects were imaged using dual-energy computer tomography to determine the presence and composition of urolithiasis. The prevalence of urolithiasis was 59% and affected patients generally had multiple stones, often with more than one component: struvite (33%), calcium oxalate (31%) and cystine (22%). Hypercalciuria was present in 78% of subjects and calcium-containing urolithiasis was associated with reduced femoral neck Z scores.

Quantifying Benefit of Autologous Transplantation for Relapsed Follicular Lymphoma Patients via Instrumental Variable Analysis.

The role of autologous stem cell transplantation (ASCT) in patients with relapsed follicular lymphoma (FL) remains controversial because of a lack of proven overall survival (OS) benefit versus nontransplant strategies. We conducted a comparative effectiveness research study involving 3 tertiary Canadian cancer centers to determine whether the ASCT-based approach used at 1 center improved OS relative to non-ASCT approaches used at the other centers. Of 1082 consecutive patients aged 18 to 60 years and diagnosed with FL from 2001 to 2010, the study population included 355 patients who experienced relapse from chemotherapy (center A = 96, center B = 84, center C = 175). Data were analyzed according to the instrumental variable of treatment center to control for confounding factors. The frequency of using ASCT at first or second relapse was significantly different between the centers (A = 58%, B = 7%, C = 5%, P < .001). With a median follow-up of 69.1 months, the actuarial 5-year OS rates after first chemotherapy relapse were 89%, 60%, and 60% for centers A, B, and C respectively (log rank P < .0001). Based on instrumental variable analysis, the use of ASCT at relapse 1 or 2 significantly decreased the risk of death from first relapse (HR .127, P = .004) and from initial diagnosis (HR .116, P = .004). In conclusion, for FL patients who relapse after chemotherapy, these results strongly support more frequent use of ASCT at first or second relapse.

Treatment of patients with secondary central nervous system lymphoma with high-dose busulfan/thiotepa-based conditioning and autologous stem cell transplant.

Although the survival rates are extremely low for patients with secondary central nervous system lymphoma (SCNSL) treated with conventional chemotherapy and radiotherapy, more encouraging outcomes have recently been reported in small series with high-dose (HD) therapy and autologous stem cell transplant (ASCT). The optimal HD regimen for SCNSL is unknown. Despite reports of thiotepa/busulfan-based conditioning for primary CNS lymphoma, very little data exist regarding the use of this regimen for SCNSL. We analyzed 23 patients with SCNSL (median age 62 years) who underwent ASCT at two Alberta centers using thiotepa, busulfan, cyclophosphamide (TBC) in six patients prior to 2011 and rituximab-busulfan, melphalan, thiotepa (R-BuMelTt) in 17 patients after 2011. At a median follow-up of 27.8 months (4.2-113.6), the 2-year actuarial rate of progression-free survival was 76.1%. In conclusion, our results demonstrate encouraging survival outcomes for patients with SCNSL treated with R-BuMelTt and ASCT.

Comparative effectiveness analysis of different salvage therapy intensities used for diffuse large B-cell lymphoma in Northern or Southern Alberta: an instrumental variable analysis.

To date, no clinical trial has addressed salvage therapy intensity for relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We sought to determine whether the more intensive salvage chemotherapy approach used in Southern Alberta (SAB) compared to the conventional dose salvage approach used in Northern Alberta (NAB) affects the rates of autologous stem cell transplant (ASCT) and survival in patients with relapsed DLBCL. Using instrumental variable analysis, we examined 147 consecutive patients with relapsed/refractory DLBCL from 2004 to 2010 who received salvage therapy in SAB (n = 70) or NAB (n = 77). Patients treated in SAB had higher rates of: salvage chemotherapy response (85.0% vs. 54.0%, p = 0.001), ASCT (61.4% vs. 41.6%, p = 0.016) and 4-year overall survival (41% vs. 20%, p = 0.002) than those in NAB, respectively. This study supports the hypothesis that selective use of intensive salvage chemotherapy leads to higher rates of ASCT and survival in this population.