Predictors of Tumor Dynamics Over a 6-Week Course of Concurrent Chemoradiotherapy for Glioblastoma and the Effect on Survival.

PURPOSE: We present the final analyses of tumor dynamics and their prognostic significance during a 6-week course of concurrent chemoradiotherapy for glioblastoma in the Glioblastoma Longitudinal Imaging Observational study. METHODS AND MATERIALS: This is a prospective serial magnetic resonance imaging study in 129 patients with glioblastoma who had magnetic resonance imaging obtained at radiation therapy (RT) planning (F0), fraction 10 (F10), fraction 20 (F20), and 1-month post-RT. Tumor dynamics assessed included gross tumor volume relative to F0 (Vrel) and tumor migration distance (dmigration). Covariables evaluated included: corpus callosum involvement, extent of surgery, O6-methylguanine-DNA-methyltransferase methylation, and isocitrate dehydrogenase mutation status. RESULTS: The median Vrel were 0.85 (range, 0.25-2.29) at F10, 0.79 (range, 0.09-2.22) at F20, and 0.78 (range, 0.13-4.27) at 1 month after completion of RT. The median dmigration were 4.7 mm (range, 1.1-20.4 mm) at F10, 4.7 mm (range, 0.8-20.7 mm) at F20, and 6.1 mm (range, 0.0-45.5 mm) at 1 month after completion of RT. Compared with patients who had corpus callosum involvement (n = 26), those without corpus callosum involvement (n = 103) had significant Vrel reduction at F20 (P = .03) and smaller dmigration at F20 (P = .007). Compared with patients who had biopsy alone (n = 19) and subtotal resection (n = 71), those who had gross total resection (n = 38) had significant Vrel reduction at F10 (P = .001) and F20 (P = .001) and a smaller dmigration at F10 (P = .03) and F20 (P = .002). O6-Methylguanine-DNA-methyltransferase methylation and isocitrate dehydrogenase mutation status were not significantly associated with tumor dynamics. The median progression-free survival and overall survival (OS) were 8.5 months (95% CI, 6.9-9.9) and 20.4 months (95% CI, 17.6-25.2). In multivariable analyses, patients with Vrel ≥ 1.33 at F10 had worse OS (hazard ratio [HR], 4.6; 95% CI, 1.8-11.4; P = .001), and patients with dmigration ≥ 5 mm at 1-month post-RT had worse progression-free survival (HR, 1.76; 95% CI, 1.08-2.87) and OS (HR, 2.2; 95% CI, 1.2-4.0; P = .007). CONCLUSIONS: Corpus callosum involvement and extent of surgery are independent predictors of tumor dynamics during RT and can enable patient selection for adaptive RT strategies. Significant tumor enlargement at F10 and tumor migration 1-month post-RT were associated with poorer OS.

Utility of molecular markers in predicting local control specific to lung cancer spine metastases treated with stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: We report outcomes following spine stereotactic body radiotherapy (SBRT) in metastatic non-small cell lung cancer (NSCLC) and the significance of programmed death-ligand 1 (PD-L1) status, epidermal growth factor receptor (EGFR) mutation and timing of immune check point inhibitors (ICI) on local failure (LF). MATERIALS AND METHODS: 165 patients and 389 spinal segments were retrospectively reviewed from 2009 to 2021. Baseline patient characteristics, treatment and outcomes were abstracted. Primary endpoint was LF and secondary, overall survival (OS) and vertebral compression fracture (VCF). Multivariable analysis (MVA) evaluated factors predictive of LF and VCF. RESULTS: The median follow-up and OS were: 13.0 months (range, 0.5-95.3 months) and 18.4 months (95% CI 11.4-24.6). 52.1% were male and 76.4% had adenocarcinoma. Of the 389 segments, 30.3% harboured an EGFR mutation and 17.0% were PD-L1 ≥ 50%. The 24 months LF rate in PD-L1 ≥ 50% vs PD-L1 < 50% was 10.7% vs. 38.0%, and in EGFR-positive vs. negative was 18.1% vs. 30.0%. On MVA, PD-L1 status of ≥ 50% (HR 0.32, 95% CI 0.15-0.69, p = 0.004) significantly predicted for lower LF compared to PD-L1 < 50%. Lower LF trend was seen with ICI administration peri and post SBRT (HR 0.41, 95% CI 0.16-1.05, p = 0.062). On MVA, polymetastatic disease (HR 3.28, 95% CI 1.84-5.85, p < 0.0001) and ECOG ≥ 2 (HR 1.87, 95% CI 1.16-3.02, p = 0.011) significantly predicted for worse OS and absence of baseline VCF predicted for lower VCF rate (HR 0.20, 95% CI 0.10-0.39, p < 0.0001). CONCLUSION: We report a significant association of PD-L1 ≥ 50% status on improved LC rates from spine SBRT in NSCLC patients.

Outcomes and adverse events in older acute lymphoblastic Leukemia patients treated with a pediatric-inspired protocol with Pegylated or native Asparaginase.

This retrospective report presents the outcomes and adverse events (AEs) observed in 73 patients aged 60 years or older diagnosed with Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia (Ph-negative ALL) treated with a pediatric-inspired protocol incorporating either Pegylated (PEG-ASP) or Native Asparaginase (EC-ASP). Notably, 61% of patients experienced AEs of Grade III-IV severity. The most prevalent AEs included thrombosis (35.6%), febrile neutropenia (38.4%), and transaminitis (34.2%). AEs did not translate into significant differences concerning overall survival, leukemia-free survival, or early mortality. Furthermore, we observed a reduction in early mortality rates (11% vs. 20%) and an increase in median overall survival (54 vs. 48 months) compared to our previous data. These findings suggest that the utilization of a pediatric-inspired chemotherapy protocol, with ASP, is an effective and well-tolerated therapeutic option for older patients with Ph-negative ALL. However, it emphasizes the importance of diligent monitoring and close follow-up throughout treatment.

Magnetic Resonance Imaging Frequency After Stereotactic Body Radiation Therapy for Spine Metastases.

PURPOSE: Stereotactic body radiation therapy (SBRT) is increasingly being used to treat spine metastases. Current post-SBRT imaging surveillance strategies in this patient population may benefit from a more data-driven and personalized approach. The objective of this study was to develop risk-stratified post-SBRT magnetic resonance imaging (MRI) surveillance strategies using quantitative methods. METHODS AND MATERIALS: Adult patients with bony spine metastases treated with SBRT between 2008 and 2021 and who had at least 2 follow-up spine MRIs were reviewed retrospectively. A recursive partitioning analysis model was developed to separate patients into different risk categories for post-SBRT progression anywhere within the spine. Imaging intervals were derived for each risk category using parametric survival regression based on multiple expected spine progression rates per scan. RESULTS: A total of 446 patients and 1039 vertebral segments were included. Cumulative incidence of spine progression was 19.2% at 1 year, 26.7% at 2 years, and 35.3% at 4 years. The internally validated risk stratification model was able to divide patients into 3 risk categories based on epidural disease, paraspinal disease, and Spinal Instability Neoplastic Score category. The 4-year risk of spine progression was 23.4%, 39.0%, and 51.8%, respectively, for the low-, intermediate-, and high-risk groups. Using an expected per-scan spine progression rate of 3.75%, the low-risk group would require follow-up scans every 6.0 months (95% CI, 4.9-7.6) and the intermediate-risk group would require surveillance every 3.1 months (95% CI, 2.6-3.7). At an expected spine progression rate of 5%, the high-risk group would require surveillance every 1.3 months (95% CI, 1.1-1.6) during the first 13.2 months after SBRT and every 5.9 months thereafter (95% CI, 2.8-12.3). CONCLUSIONS: Data-driven follow-up MRI surveillance intervals at a range of expected spine progression rates have been determined for patients at different risks of spine progression based on an internally validated, single-institution risk stratification model.

Stereotactic Body Radiation Therapy for Sacral Metastases: Deviation From Recommended Target Volume Delineation Increases the Risk of Local Failure.

PURPOSE: Although spine stereotactic body radiation therapy (SBRT) is considered a standard of care in the mobile spine, mature evidence reporting outcomes specific to sacral metastases is lacking. Furthermore, there is a need to validate the existing sacral SBRT international consensus contouring guidelines to define the optimal contouring approach. We report mature rates of local failure (LF), adverse events, and the effect of contouring deviations in the largest experience to date specific to sacrum SBRT. METHODS AND MATERIALS: Consecutive patients who underwent sacral SBRT from 2010 to 2021 were retrospectively reviewed. The primary endpoint was magnetic resonance imaging-based LF with a focus on adherence to target volume contouring recommendations. Secondary endpoints included vertebral compression fracture and neural toxicity. RESULTS: Of the 215 sacrum segments treated in 112 patients, most received 30 Gy/4 fractions (51%), 24 Gy/2 fractions (31%), or 30 Gy/5 fractions (10%). Sixteen percent of segments were nonadherent to the consensus guideline with a more restricted target volume (undercontoured). The median follow-up was 21.4 months (range, 1.5-116.9 months). The cumulative incidence of LF at 1 and 2 years was 18.4% and 23.1%, respectively. In those with guideline adherent versus nonadherent contours, the LF rate at 1 year was 15.1% versus 31.4% and at 2 years 18.8% versus 40.0% (hazard ratio [HR], 2.5; 95% CI, 1.4-4.6; P = .003), respectively. On multivariable analysis, guideline nonadherence (HR, 2.4; 95% CI, 1.3-4.7; P = .008), radioresistant histology (HR, 2.4; 95% CI, 1.4-4.1; P < .001), and extraosseous extension (HR, 2.5; 95% CI, 1.3-4.7; P = .005) predicted for an increased risk of LF. The cumulative incidence of vertebral compression fracture was 7.1% at 1 year and 12.3% at 2 years. Seven patients (6.3%) developed peripheral nerve toxicity, of whom 4 had been previously radiated. CONCLUSIONS: Sacral SBRT is associated with high efficacy rates and an acceptable toxicity profile. Adhering to consensus guidelines for target volume delineation is recommended to reduce the risk of LF.

Dual T cell depletion for graft versus host disease prevention in peripheral blood haploidentical hematopoietic cell transplantation for adults with hematological malignancies.

The ideal immunosuppressive agents to complement post-transplant cyclophosphamide (PTCy) in PBSC-based haploidentical hematopoietic cell transplantation (haplo-HCT) remain debated. This study looks at our experience with ATG-PTCy-Cyclosporine (CsA) prophylaxis in PB haplo-HCT since 2015. Between October 2015 and December 2021, 157 adults underwent haploidentical hematopoietic cell transplantation (haplo-HCT) using a GVHD prophylaxis regimen comprising rabbit-ATG, PTCy, and CsA. Among these patients, 76.4% received a total ATG dose of 4.5 mg/kg, and 23.5% received 2 mg/kg. T-cell replete peripheral blood stem cell (PBSC) grafts were infused on day 0. The study reported a median follow-up of 32 months (range 0.3-61.64) for survivors. The cumulative incidence of grade II-IV and grade III-IV acute GVHD at day +100 was 26.3% and 9.5%, respectively. Moderate/severe chronic GVHD at 1 year was 19.9%. The 2-year overall survival (OS) was 49.4%, with a relapse-free survival (RFS) of 44.6%. In multivariate analysis, older patients, and those with high/very-high disease risk indices (DRI) were at higher risk for worse OS and higher non-relapse mortality (NRM). The study confirms that using PTCy and ATG (4.5 mg/kg), alongside CsA is safe and effective in preventing GVHD when using peripheral blood as the stem cell source in haploidentical hematopoietic cell transplantation (haplo-HCT).

Outcomes of Antithymocyte Globulin-Post-Transplantation Cyclophosphamide-Cyclosporine-Based versus Antithymocyte Globulin-Based Prophylaxis for 10/10 HLA-Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplantation.

In 2015, dual T cell depletion with antithymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) combined with cyclosporine A (CsA) replaced our prior institutional graft-versus-host disease (GVHD) prophylaxis regimen of 4.5 mg/kg ATG, CsA, and mycophenolate mofetil (MMF) (ATG-based) in 10/10 HLA-matched unrelated donor (MUD) peripheral blood allogeneic hematopoietic stem cell transplantation (allo-HCT). The initial ATG dose of 4.5 mg/kg [ATG(4.5)/PTCy] was reduced to 2 mg/kg [ATG(2)/PTCy] in 2018. This study compares the results obtained from 444 adults undergoing MUD allo-HCT at our institution who received ATG(4.5)/PTCy (n = 127) or ATG(2)/PTCy (n = 223) with those who received ATG-based prophylaxis without PTCy (n = 84). The rates of grade II-IV and grade III-IV acute GVHD (aGVHD) at day +100 and moderate/severe chronic GVHD (cGVHD) at 1 year were 35.7%, 21.6%, and 14.7%, respectively, in patients receiving ATG-based prophylaxis without PTCy; 16.5%, 4.9%, and 4.3% in patients receiving ATG(4.5)/PTCy; and 23.3% (P = .004), 8.0% (P < .001), and 14.1% (P =.006) in patients receiving ATG(2)/PTCy. One-year overall survival (OS), nonrelapse mortality (NRM), and GVHD-free relapse-free survival (GRFS) were 69.8%, 25.3%, and 52.0%, respectively, for patients receiving ATG-based prophylaxis without PTCy; 82.7%, 17.3%, and 59.8% for patients receiving ATG(4.5)/PTCy; and 78.3% (P = .446), 14.7% (P = 101), and 56.2% (P = .448) for patients receiving ATG(2)/PTCy. On univariate analyses, the use of ATG(2)/PTCy was associated with a lower risk of NRM (hazard ratio, .54; P = .023) compared with the use of ATG-based prophylaxis without PTCy. ATG(2)/PTCy prophylaxis effectively prevents GVHD and is associated with comparable relapse risk, OS, and GRFS as seen with ATG(4.5)/PTCy and ATG-based prophylaxis without PTCy.

Propensity-matched Analysis of Open Versus Robotic Primary Retroperitoneal Lymph Node Dissection for Clinical Stage II Testicular Cancer.

BACKGROUND: Open retroperitoneal lymph node dissection (O-RPLND) is the accepted standard surgical approach to treat retroperitoneal nodal disease in testis cancer. Increasingly, robotic RPLND (R-RPLND) is being performed due to the potential for lower blood loss, shorter length of stay, and accelerated recovery. OBJECTIVE: We have performed a propensity score matching (PSM) analysis comparing the survival and perioperative outcomes of O- and R-RPLND. DESIGN, SETTING, AND PARTICIPANTS: Analyzing the data from all patients who underwent primary RPLND at our center between 1990 and 2022, we used PSM to create a 2:1 (O-RPLND:R-RPLND) matched cohort. INTERVENTION: Primary O-RPLND versus R-RPLND. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was time to relapse. The secondary endpoints included operating time, length of stay, estimated blood loss (EBL), and surgical complications. Relapse-free survival rates were calculated using the Kaplan-Meier method, and log-rank tests were used to compare perioperative outcomes of O-RPLND versus R-RPLND. KEY FINDINGS AND LIMITATIONS: A total of 178 patients underwent primary RPLND: 137 O-RPLND and 41 R-RPLND. After PSM, 26 patients in the R-RPLND group were matched with 38 in the O-RPLND group. After matching, no significant baseline differences were noted. After a median follow-up of 23.5 mo (interquartile range 4.4-59.2), one (3.8%) relapse was noted in the R-RPLND group versus three (7.8%) in the O-RPLND group; however, this was not significant (hazard ratio 0.65, 95% confidence interval 0.07-6.31, p = 0.7097). No in-field relapses occurred in either cohort. R-RPLND was associated with a shorter length of stay (1 vs 5 d, p < 0.0001) and lower EBL (200 vs 300 ml, p = 0.032), but longer operative time (8.8 vs 4.3 h, p < 0.0001). CONCLUSIONS: R-RPLND offers low morbidity and improved perioperative outcomes, while maintaining oncologic efficacy of the open approach. PATIENT SUMMARY: To the best of our knowledge, this is the first study to compare open and robotic retroperitoneal lymph node dissection (R-RPLND) using a propensity score-matched system. We encourage the discussion and inclusion of primary R-RPLND into the standard of care algorithm for patients with de novo clinical stage (CS) II and relapsed CS I with CS II equivalent disease.

Dose-Escalated Radiation Therapy Is Associated With Improved Outcomes for High-Grade Meningioma.

PURPOSE: The optimal modern radiation therapy (RT) approach after surgery for atypical and malignant meningioma is unclear. We present results of dose escalation in a single-institution cohort spanning 2000 to 2021. METHODS AND MATERIALS: Consecutive patients with histopathologic grade 2 or 3 meningioma treated with RT were reviewed. A dose-escalation cohort (≥66 Gy equivalent dose in 2-Gy fractions using an α/ß = 10) was compared with a standard-dose cohort (<66 Gy). Outcomes were progression-free survival (PFS), cause-specific survival, overall survival (OS), local failure (LF), and radiation necrosis. RESULTS: One hundred eighteen patients (111 grade 2, 94.1%) were identified; 54 (45.8%) received dose escalation and 64 (54.2%) standard dose. Median follow-up was 45.4 months (IQR, 24.0-80.0 months) and median OS was 9.7 years (Q1: 4.6 years, Q3: not reached). All dose-escalated patients had residual disease versus 65.6% in the standard-dose cohort (P < .001). PFS at 3, 4, and 5 years in the dose-escalated versus standard-dose cohort was 78.9%, 72.2%, and 64.6% versus 57.2%, 49.1%, and 40.8%, respectively, (P = .030). On multivariable analysis, dose escalation (hazard ratio [HR], 0.544; P = .042) was associated with improved PFS, whereas ≥2 surgeries (HR, 1.989; P = .035) and older age (HR, 1.035; P < .001) were associated with worse PFS. The cumulative risk of LF was reduced with dose escalation (P = .016). Multivariable analysis confirmed that dose escalation was protective for LF (HR, 0.483; P = .019), whereas ≥2 surgeries before RT predicted for LF (HR, 2.145; P = .008). A trend was observed for improved cause-specific survival and OS in the dose-escalation cohort (P < .1). Seven patients (5.9%) developed symptomatic radiation necrosis with no significant difference between the 2 cohorts. CONCLUSIONS: Dose-escalated RT with ≥66 Gy for high-grade meningioma is associated with improved local control and PFS with an acceptable risk of radiation necrosis.

AML with CEBPA mutations: A comparison of ICC and WHO-HAEM5 criteria in patients with 20% or more blasts.

AML with CEBPA mutation and AML with in-frame bZIP CEBPA mutations define favorable-risk disease entities in the proposed 5th edition of the World Health Organization Classification (WHO-HAEM5) and the International Consensus Classification (ICC), respectively. However, the impact of these new classifications on clinical practice remains unclear. We sought to assess the differences between the ICC and WHO-HAEM5 for AML with CEBPA mutation. 741 AML patients were retrospectively analyzed. Cox proportional-hazard regression was used to identify factors predictive of outcome. A validation cohort from the UK-NCRI clinical trials was used to confirm our findings. 81 (11%) AML patients had CEBPA mutations. 39 (48%) patients met WHO-HAEM5 criteria for AML with CEBPA mutation, among which 30 (77%) had biallelic CEBPA mutations and 9 (23%) had a single bZIP mutation. Among the 39 patients who met WHO-HAEM5 criteria, 25 (64%) also met ICC criteria. Compared to patients only meeting WHO-HAEM5 criteria, patients with in-frame bZIP CEBPA mutations (ie. meeting both WHO-HAEM5 and ICC criteria) were younger, had higher bone marrow blast percentages and CEBPA mutation burden, infrequently harboured 2022 ELN high-risk genetic features and co-mutations in other genes, and had superior outcomes. The associations in clinicopathological features and outcomes between the CEBPA-mutated groups were validated in the UK-NCRI cohort. Our study indicates that in-frame bZIP CEBPA mutations are the critical molecular aberrations associated with favorable outcomes in AML patients treated with curative intent chemotherapy. Compared to WHO-HAEM5, the ICC identifies a more homogenous group of CEBPA-mutated AML patients with favorable outcomes.

Final report of TKI discontinuation trial with dasatinib for the second attempt of treatment-free remission after failing the first attempt with imatinib: Treatment-free Remission Accomplished by Dasatinib (TRAD) study.

Multiple studies have reported a significant treatment-free remission (TFR) rate of 50%-60% in patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitor (TKI) therapy. However, the remaining half of these patients still require re-initiation of TKI therapy for leukaemia control. It remains unclear if TKI drugs should be switched for re-therapy in patients who failed the first TFR (TFR1) attempt. Our study attempted to determine whether dasatinib therapy after TFR1 failure post-imatinib discontinuation could improve the likelihood of TFR2. Of 59 patients who lost molecular response after imatinib discontinuation for TFR1, 55 patients (93.2%) were treated with dasatinib, of whom 49 (89.1%) regained MR4.5 or deeper response, with a median time of 1.85 months to achieve MR4.5. Dasatinib was discontinued in 35 patients for TFR2 attempt, of whom 26 patients (74.28%) lost MMR and 6 (17.14%) MR4. Risk factor analysis for the TFR2 after dasatinib discontinuation suggested three significant factors: (1) doubling time of BCR::ABL1 transcript following TFR1 attempt, (2) rapid regaining of molecular response following dasatinib therapy and (3) undetectable BCR::ABL1 transcript prior to TFR2 attempt. The present study showed that dasatinib does not increase the TFR2 rate in general, but a selected group of patients could benefit from this approach.

HCT frailty scale for younger and older adults undergoing allogeneic hematopoietic cell transplantation.

The HCT Frailty Scale is an easy prognostic tool composed of (a) Clinical Frailty Scale; (b) Instrumental Activities of Daily Living; (c) Timed-up-and-Go test; (d) Grip Strength; (e) Self-Health Rated Questionnaire; (f) Falls tests; (g) Albumin and C-reactive protein levels. This scale was designed to classify allogeneic hematopoietic cell transplant (alloHCT) candidates into fit, pre-frail and frail groups, irrespective of age. This study evaluates the ability of this frailty classification to predict overall survival (OS) and non-relapse mortality (NRM) in adult patients of all ages, in a prospective sample of 298 patients transplanted between 2018 and 2020. At first consultation, 103 (34.6%) patients were fit, 148 (49.7%) pre-frail, and 47 (15.8%) were frail. The 2-year OS and NRM of the three groups were 82.9%, 67.4%, and 48.3% (P < 0.001), and 5.4%, 19.2%, and 37.7% (P < 0.001). For patients younger than 60 years (n = 174), the 2-year OS and NRM of fit, pre-frail, and frail groups were 88.4%, 69.3% and 53.1% (P = 0.002), and 5.8%, 22.8%, and 34.8% (P = 0.005), respectively; and in patients older than 60 (n = 124), OS and NRM were 75.5%, 63.8% and 41.4% (P = 0.006), and 4.9%, 16.4%, and 42.1% (P = 0.001). In conclusion, frailty predicted worse transplant outcomes in both younger and older adults.

High sensitivity c-reactive protein and circulating biomarkers of endothelial dysfunction in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) have revolutionized the management of patients with chronic myelogenous leukemia (CML); however, they may cause cardiovascular (CV) toxicities. In this cross-sectional study, we explored whether high-sensitivity C-reactive protein (hsCRP) and novel markers of vascular dysfunction were associated with exposure to specific TKIs, in 262 CML patients. Hs-CRP level was not associated with CML disease activity or treatment with a specific TKI. Body mass index (OR: 1.15, 95% CI: 1.108-1.246; p < 0.001) and CML duration (OR: 1.004, 95% CI: 1.001-1.008; p = 0.024) were independently associated with higher hs-CRP. In exploratory analyses, novel endothelial-centric markers (e.g. ET-1 and VCAM-1) were differential across the various TKIs, particularly amongst nilotinib- and ponatinib-treated patients. While Levels of hs-CRP do not appear to be correlated with specific TKIs, circulating markers of vascular dysfunction were altered in patients treated with specific TKIs and should be explored as potential markers of TKI-associated CV risk.

Impact of Geographical Distance from Quaternary Treatment Center on Clinical Trial Participation, Intensive Induction Chemotherapy, and Outcomes in Patients with Newly Diagnosed Acute Myeloid Leukemia.

INTRODUCTION: Care for patients with acute myeloid leukemia (AML) is centralized in the Ontario single-payer public healthcare system, with intensive induction chemotherapy and clinical trials only offered at specialized cancer centers with large catchment areas. METHODS: We therefore conducted a retrospective single-center review of all AML patients assessed at a large specialized cancer center in Ontario, Canada. RESULTS: Between 2012 and 2017, 1,310 patients were assessed by our center for upfront AML therapy. The median distance was 33.1 km, with 29% of patients living more than 50 km away from the center. There was no significant difference in probability of intensive induction chemotherapy or clinical trial by distance from center, both in univariate and multivariable analysis adjusting for age, sex, cytogenetics and molecular testing, and performance status. There was no significant difference in overall survival by distance from center on univariate and multivariable analysis. CONCLUSION: In conclusion, geographic distance from treatment center does not appear to impact choice of upfront therapy, participation in clinical trials, or clinical outcomes in this study of newly diagnosed patients with AML treated in a single-payer environment.

TP53 Mutations in AML Patients Are Associated with Dismal Clinical Outcome Irrespective of Frontline Induction Regimen and Allogeneic Hematopoietic Cell Transplantation.

TP53 mutations are associated with extremely poor outcomes in acute myeloid leukemia (AML). The outcomes of patients with TP53-mutated (TP53MUT) AML after different frontline treatment modalities are not well established. Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative procedure for AML; however, long-term outcomes among patients with TP53MUT AML after allo-HCT are dismal, and the benefit of allo-HCT remains controversial. We sought to evaluate the outcomes of patients with TP53MUT AML after treatment with different frontline induction therapies and allo-HCT. A total of 113 patients with TP53MUT AML were retrospectively evaluated. Patients with TP53MUT AML who received intensive or azacitidine-venetoclax induction had higher complete remission rates compared to patients treated with other hypomethylating-agent-based induction regimens. However, OS and EFS were not significantly different among the induction regimen groups. Allo-HCT was associated with improved OS and EFS among patients with TP53MUT AML; however, allo-HCT was not significantly associated with improved OS or EFS in time-dependent or landmark analysis. While the outcomes of all patients were generally poor irrespective of therapeutic strategy, transplanted patients with lower TP53MUT variant allele frequency (VAF) at the time of diagnosis had superior outcomes compared to transplanted patients with higher TP53 VAF. Our study provides further evidence that the current standards of care for AML confer limited therapeutic benefit to patients with TP53 mutations.

A longitudinal multidimensional rehabilitation program for patients undergoing allogeneic blood and marrow transplantation (CaRE-4-alloBMT): Protocol for a phase II feasibility pilot randomized controlled trial.

BACKGROUND: Allogeneic blood and marrow transplantation (alloBMT) is a curative treatment for blood cancers associated with various treatment-related adverse events and morbidities. Current rehabilitation programs are limited for patients undergoing alloBMT and research is urgently needed to test the acceptability and effectiveness of these programs. In response, we developed a 6-month multidimensional longitudinal rehabilitation program that spans from pre transplant to 3 months post transplant discharge (CaRE-4-alloBMT). METHODS: This study is a phase II randomized controlled trial (RCT) conducted at the Princess Margaret Cancer Centre in patients undergoing alloBMT. A total of 80 patients stratified by frailty score will be randomized to receive usual care (n = 40) or CaRE-4-alloBMT plus usual care (n = 40). The CaRE-4-alloBMT program includes individualized exercise prescriptions, access to online education through a dedicated self-management platform, wearable technology for remote monitoring, and remote tailored clinical support. Feasibility will be assessed by examining the recruitment and retention rates and adherence to the intervention. Safety events will be monitored. Acceptability of the intervention will be assessed through qualitative interviews. Secondary clinical outcomes will be collected through questionnaires and physiological assessments at baseline (T0, 2-6 weeks pre-transplant), transplant hospital admission (T1), hospital discharge (T2), and 3 months post-discharge (T3). CONCLUSION: This pilot RCT study will determine the feasibility and acceptability of the intervention and study design and will inform full-scale RCT planning.

30 Gy in 4 Stereotactic Body Radiotherapy Fractions for Complex Spinal Metastases: Mature Outcomes Supporting This Novel Regimen.

BACKGROUND AND OBJECTIVES: We designed a 30 Gy in 4 fractions stereotactic body radiotherapy protocol, as an alternative option to our standard 2-fraction approach, for primarily large volume, multilevel, or previously radiated spinal metastases. We report imaging-based outcomes of this novel fractionation scheme. METHODS: The institutional database was reviewed to identify all patients who underwent 30 Gy/4 fractions from 2010 to 2021. Primary outcomes were magnetic resonance-based vertebral compression fracture (VCF) and local failure per treated vertebral segment. RESULTS: We reviewed 245 treated segments in 116 patients. The median age was 64 years (range, 24-90). The median number of consecutive segments within the treatment volume was 2 (range, 1-6), and the clinical target volume (CTV) was 126.2 cc (range, 10.4-863.5). Fifty-four percent had received at least 1 previous course of radiotherapy, and 31% had previous spine surgery at the treated segment. The baseline Spinal Instability Neoplastic Score was stable, potentially unstable, and unstable for 41.6%, 51.8%, and 6.5% of segments, respectively. The cumulative incidence of local failure was 10.7% (95% CI 7.1-15.2) at 1 year and 16% (95% CI 11.5-21.2) at 2 years. The cumulative incidence of VCF was 7.3% (95% CI 4.4-11.2) at 1 year and 11.2% (95% CI 7.5-15.8) at 2 years. On multivariate analysis, age ≥68 years ( P = .038), CTV volume ≥72 cc ( P = .021), and no previous surgery ( P = .021) predicted an increased risk of VCF. The risk of VCF for CTV volumes <72 cc/≥72 cc was 1.8%/14.6% at 2 years. No case of radiation-induced myelopathy was observed. Five percent of patients developed plexopathy. CONCLUSION: 30 Gy in 4 fractions was safe and efficacious despite the population being at increased risk of toxicity. The lower risk of VCF in previously stabilized segments highlights the potential for a multimodal treatment approach for complex metastases, especially for those with a CTV volume of ≥72 cc.

Impact of mutations on pregnancy outcome in patients with myeloproliferative neoplasms.

The impact of driver and other somatic mutations on pregnancy outcomes is unknown. The purpose of this study was to report the management and outcome of pregnancies in a cohort of myeloproliferative neoplasms (MPN) patients, particularly to evaluate the impact of somatic mutations. The cohort included consecutive patients with MPN who had a least one confirmed pregnancy. The primary outcome was live births. Secondary outcomes were thrombotic and major bleeding events. Between 2010 and 2021, 29 pregnancies occurred in 24 individuals with MPN. Aspirin was used in 24 cases (83%) and interferon alfa in five (17%). There were 24 live births (83%). There were three thrombotic events, two antepartum and one postpartum. Miscarriages and thrombotic events occurred in JAK2-mutated and triple negative, but not CALR-mutated, MPN. Additional somatic mutations were rare, and there were no apparent associations with pregnancy loss or complications. While JAK2 V617F is associated with an increased risk of thrombosis, its impact on pregnancy outcome has been inconsistently reported. The association between triple negative MPN and adverse pregnancy outcome has not previously been reported. While limited by small numbers, this study underscores the importance of describing driver and other mutations to direct optimal antenatal care in individuals with MPN.

Interferon and interferon-induced cytokines as markers of impending clinical progression in ANA+ individuals without a systemic autoimmune rheumatic disease diagnosis.

BACKGROUND: Elevated levels of interferons (IFNs) are a characteristic feature of systemic autoimmune rheumatic diseases (SARDs) and may be useful in predicting impending symptomatic progression in anti-nuclear antibody-positive (ANA+) individuals lacking a SARD diagnosis. Typically, these are measured by their effect on gene expression in the blood, which has limited their utility in clinical settings. Here, we assessed whether the measurement of serum IFN-α or selected IFN-induced cytokines accurately mirrors IFN-induced gene expression in ANA+ individuals and investigated their utility as biomarkers of clinical progression. METHODS: A total of 280 subjects were studied, including 50 ANA- healthy controls, 160 ANA+ individuals without a SARD diagnosis (96 asymptomatic, 64 with undifferentiated connective tissue disease), and 70 SARD patients. IFN-induced gene expression was measured by nanoString and cytokine levels by ELISA or Simoa. ANA+ individuals lacking a SARD diagnosis who had the new onset of SARD criteria over the subsequent 2 years were defined as progressors. RESULTS: Measurement of IFN-α levels by high-sensitivity ELISA or Simoa correlated much better with IFN-induced gene expression than measurement of CXCL-10 or Galectin-9 levels. Despite this, high CXCL-10 and Galectin-9 levels were better predictors of subsequent progression in ANA+ individuals than measures of IFN-α or IFN-induced gene expression with the optimal combination of predictive cytokines (CXCL-10 and IFN-α as measured by ELISA), resulting in a specificity and positive predictive value of 100%. CONCLUSION: Easily performed ELISA assays for CXCL-10 and IFN-α can be used to predict ANA+ individuals at high risk of imminent symptomatic progression.

Venous thromboembolism incidence associated with pegylated asparaginase (ASP) compared to the native L-ASP: A retrospective analysis with an ASP-based protocol in adult patients with acute lymphoblastic leukaemia.

Venous thromboembolism (VTE) is a well-known complication in patients with acute lymphoblastic leukaemia (ALL) receiving asparaginase (ASP)-based chemotherapy, including the ASP-intensive Dana-Farber Cancer Institute (DFCI) 91-01 protocol for adults. Since 2019, native L-ASP is no longer available in Canada and was replaced by pegylated (PEG)-ASP. To determine whether the incidence of VTE has changed since switching from L-ASP to PEG-ASP, we conducted a single-centred retrospective cohort study. We included 245 adult patients with Philadelphia chromosome negative ALL between 2011 and 2021, with 175 from the L-ASP group (2011-2019) and 70 from the PEG-ASP group (2018-2021). During Induction, 10.29% (18/175) of patients who received L-ASP developed VTE, whereas 28.57% (20/70) of patients who received PEG-ASP developed VTE (p = 0.0035; odds ratio [OR] 3.35, 95% confidence interval [CI] 1.51-7.39), after adjusting for line type, gender, history of VTE, platelets at diagnosis. Similarly, during Intensification, 13.64% (18/132) of patients had VTE on L-ASP while 34.37% (11/32) of patients on PEG-ASP developed VTE (p = 0.0096; OR 3.96, 95% CI 1.57-9.96 with multivariable analysis). We found that PEG-ASP is associated with a higher incidence of VTE compared to L-ASP, both during Induction and Intensification, despite the administration of prophylactic anticoagulation. Further VTE mitigation strategies are needed in particular for adult patients with ALL receiving PEG-ASP.