Deuterated water labeling in ibrutinib-treated patients with CLL: leukemia cell kinetics correlate with IGHV, ZAP-70, and MRD.

Deuterated ("heavy") water labeling in CLL patients demonstrates that IGHV unmutated and ZAP-70-positive patients have higher blood and tissue CLL death rates on ibrutinib therapy, resulting in lower measurable residual disease (MRD) levels with long-term ibrutinib treatment. #NCT01752426.

The DLEU2/miR-15a/miR-16-1 cluster shapes the immune microenvironment of chronic lymphocytic leukemia.

The development and progression of chronic lymphocytic leukemia (CLL) depend on genetic abnormalities and on the immunosuppressive microenvironment. We have explored the possibility that genetic drivers might be responsible for the immune cell dysregulation that shapes the protumor microenvironment. We performed a transcriptome analysis of coding and non-coding RNAs (ncRNAs) during leukemia progression in the Rag2-/-γc-/- MEC1-based xenotransplantation model. The DLEU2/miR-16 locus was found downmodulated in monocytes/macrophages of leukemic mice. To validate the role of this cluster in the tumor immune microenvironment, we generated a mouse model that simultaneously mimics the overexpression of hTCL1 and the germline deletion of the minimal deleted region (MDR) encoding the DLEU2/miR-15a/miR-16-1 cluster. This model provides an innovative and faster CLL system where monocyte differentiation and macrophage polarization are exacerbated, and T-cells are dysfunctional. MDR deletion inversely correlates with the levels of predicted target proteins including BCL2 and PD1/PD-L1 on murine CLL cells and immune cells. The inverse correlation of miR-15a/miR-16-1 with target proteins has been confirmed on patient-derived immune cells. Forced expression of miR-16-1 interferes with monocyte differentiation into tumor-associated macrophages, indicating that selected ncRNAs drive the protumor phenotype of non-malignant immune cells.

Elevated Body Mass Index Is Associated With Rotator Cuff Disease: A Systematic Review and Meta-analysis.

Purpose: To analyze the literature regarding obesity, body mass index (BMI), and rotator cuff disease (RCD). Methods: In this Systematic Review and Meta-analysis, we queried PubMed, Embase, Cochrane, Cumulative Index to Nursing & Allied Health, and Science Direct using key words (August 25, 2023). Analytic observational studies (cohort, case-control, and cross-sectional studies) with more than 30 participants per comparison group, evaluating the association between obesity and rotator cuff pathology, were eligible for inclusion. Meta-analysis was performed to quantitatively summarize associations between BMI and RCD to report odds ratios and corresponding 95% confidence intervals (CIs) for regression-based models and BMI mean differences between cases and controls. Risk Of Bias In Non-randomised Studies - of Interventions tool was used to evaluate risk of bias across all studies in the systematic review. Results: After full-text review of 248 articles, 27 presented data on obesity and RCD, and 17 qualified for meta-analysis. Individuals with RCD were 1.21 times (95% CI 1.10-1.34) as likely to have overweight and 1.44 times (95% CI 1.32-1.59) as likely to have obesity compared with those without RCD. Each 5-unit increase in BMI was associated with 35% greater odds of having rotator cuff tear (95% CI 1.06-1.71). In-depth assessment for risk of bias shows quality of studies varies greatly and highlights outcome heterogeneity, lack of temporality, confounding and selection bias as major concerns for individual studies. Conclusions: In this study, we found a positive association between elevated BMI and RCD. Level of Evidence: Level III, systematic review and meta-analysis of Level II-III studies.

Acute Lymphoblastic Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.

A Multicenter Analysis of Allogeneic Transplant Outcomes in Adults with Philadelphia-Like B-Cell Acute Lymphoblastic Leukemia in First Complete Remission.

Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subset of B-cell ALL with a poor prognosis with conventional therapies. Diagnostic challenges and lack of standardized treatment protocols contribute to suboptimal outcomes. Additionally, while allogeneic hematopoietic cell transplantation (HCT) is frequently recommended in adults with Ph-like ALL given its high-risk nature, data supporting its role remains limited. We conducted a multicenter retrospective study evaluating outcomes of adult patients undergoing HCT in first complete remission (CR1) for Ph-like ALL compared to Philadelphia chromosome positive ALL (Ph-pos) and other B-cell Philadelphia negative (Ph-neg) ALL. Data was collected from five academic centers across the US, focusing on HCT outcomes for patients with ALL. Patients undergoing HCT in CR1 between 2006 and 2021 were included. Among 673 patients, 83 (12.3%) had Ph-like ALL, while 271 (40.3%) had Ph-pos and 319 (47.4%) had Ph-neg ALL. Outcomes following HCT in CR1 for Ph-like ALL were comparable to Ph-neg ALL, with no significant differences in 3-year overall survival (66% vs. 59%, P = .1), progression-free survival (59% and 54%, P = .1), or relapse rates (22% vs. 20%, P = .7). In contrast, Ph-pos ALL had superior outcomes; 3-year OS (75%, P < .001), PFS (70%, P = .001) and relapse (12%, P = .003), this is likely attributed to tyrosine kinase inhibitor therapy. Our study suggests that HCT, coupled with effective 2nd line therapies can possibly mitigate the poor prognosis associated with Ph-like ALL and offers promising outcomes for patients with Ph-like ALL.

Risk Factor Prediction and Categorization for Glenohumeral Osteoarthritis: A Classification and Regression Tree (CART) Analysis.

OBJECTIVE: This study aimed to apply Classification and Regression Tree (CART) analysis to determine factors associated with glenohumeral osteoarthritis (GH OA) and establish specific cut-off points for risk factors based on this methodology. DESIGN: The cross-sectional study included 3,383 participants with shoulder pain. Cases were selected for GH OA. Patients with other shoulder pathologies were included as controls. 33 potential risk factors were assessed. The CART analysis was used to determine the highest-ranked risk factors associated with GH OA. Multivariable logistic regression analysis was then performed using the cut-off points obtained from the CART analysis. RESULTS: The CART analysis showed that age and body mass index (BMI) were the two most significant risk factors for GH OA. Multivariable logistic regression revealed that age categories ≥31- < 58 years (OR = 8.92), ≥58- < 64 years (OR = 20.20), and ≥ 64 years (OR = 42.20), and BMI categories ≥25-30 kg/ m2 (OR = 1.47) and ≥ 30 kg/ m2 (OR = 1.71) had higher odds of developing GH OA compared to age < 31 years and BMI <25 kg/m2. CONCLUSION: This was the first study to use CART analysis to evaluate significant risk factors for GH OA and establish cut-off points for increased risk. The findings present age categories that are distinct from the arbitrary age groups used in previous studies.

Longitudinal follow up of a phase 2 trial of venetoclax added to hyper-CVAD, nelarabine and pegylated asparaginase in patients with T-cell acute lymphoblastic leukemia and lymphoma.

Optimal frontline use of active agents in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is prudent to improve outcomes. We report the long-term follow-up of the phase 2 trial of HyperCVAD with nelarabine and pegylated asparaginase (Original cohort). In the latest protocol iteration venetoclax was added to the induction/consolidation regimen (Venetoclax cohort). Eligible patients were adults with untreated T-ALL/LBL or after minimal therapy and with adequate organ function. Primary endpoint of this analysis was improvement in 2-year progression free survival (PFS) and overall survival (OS) with venetoclax. From Aug 2007 to Dec 2024, 145 patients, at a median age of 35.4 years, were treated; 46 (33.8%) were in the venetoclax cohort. At median follow-up (mFU) of 62.4 months, 5-year PFS, duration of response (DOR), and OS were 63.7%, 72.0% and 66.2% respectively. In the venetoclax cohort (mFU 24.4 months) 2-year PFS (87.9% versus 64.1%, p = 0.03) and 2-year DOR (93.6% versus 69.2%, p = 0.005) were superior to the original cohort (mFU 89.4 months) and 2-year OS appeared better (87.8% versus 73.9%, p = 0.16). Febrile neutropenia was the most common serious adverse event, seen in 60% patients. The addition of venetoclax to HyperCVAD-nelarabine-pegylated asparaginase was tolerable and led to improvement in DOR and PFS.

A phase 2 trial of mini-hyper-CVD, blinatumomab, and ponatinib in Philadelphia positive acute lymphoblastic leukemia.

Twenty adults with newly diagnosed (ND) or relapsed/refractory (RR) Ph-positive acute lymphoblastic leukemia (ALL), or chronic myeloid leukemia in lymphoid blast phase (CML-LBP), were treated with mini-hyperCVD, ponatinib, and blinatumomab. Complete molecular response was achieved in 78% of ND patients, while CR/CRi was achieved in 100% of RR and CML-LBP. The 3-year overall survival rate was 76% (95% CI, 47%-90%).

Impact of Age on Pharmacogenomics and Treatment Outcomes of B-Cell Acute Lymphoblastic Leukemia.

PURPOSE: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. METHODS: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. RESULTS: Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2-, DUX4-, and KMT2A-rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. CONCLUSION: Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclax-resistant chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the Bcell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax. To test this hypothesis, we conducted a pre-clinical investigation of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition to minimize platelet toxicity. This study demonstrated that LP-118 induces efficient BAK activation, cytochrome C release, and apoptosis in both venetoclax naïve and resistant CLL cells. Significantly, LP-118 is effective in cell lines expressing the BCL2 G101V mutation and in cells expressing BCLXL but lacking BCL2 dependence. Using an immunocompetent mouse model, Eµ-TCL1, LP-118 demonstrates low platelet toxicity, which hampered earlier BCLXL inhibitors. Finally, LP-118 in the RS4;11 and OSU-CLL xenograft models results in decreases in tumor burden and survival advantage, respectively. These results provide a mechanistic rationale for the evaluation of LP-118 for the treatment of venetoclax responsive and relapsed CLL.

Menin inhibitors in pediatric acute leukemia: a comprehensive review and recommendations to accelerate progress in collaboration with adult leukemia and the international community.

Aberrant expression of HOX and MEIS1 family genes, as seen in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutated leukemias leads to arrested differentiation and leukemia development. HOX family genes are essential gatekeepers of physiologic hematopoiesis, and their expression is regulated by the interaction between KMT2A and menin. Menin inhibitors block this interaction, downregulate the abnormal expression of MEIS1 and other transcription factors and thereby release the differentiation block. Menin inhibitors show significant clinical efficacy against KMT2A-rearranged and NPM1-mutated acute leukemias, with promising potential to address unmet needs in various pediatric leukemia subtypes. In this collaborative initiative, pediatric and adult hematologists/oncologists, and stem cell transplant physicians have united their expertise to explore the potential of menin inhibitors in pediatric leukemia treatment internationally. Our efforts aim to provide a comprehensive clinical overview of menin inhibitors, integrating preclinical evidence and insights from ongoing global clinical trials. Additionally, we propose future international, inclusive, and efficient clinical trial designs, integrating pediatric populations in adult trials, to ensure broad access to this promising therapy for all children and adolescents with menin-dependent leukemias.

Peripheral Nerve Stimulation of the Axillary Nerve Improves Chronic Shoulder Pain and Dysfunction Following Reverse Total Shoulder Arthroplasty: A Case Report.

ABSTRACT: Reverse total shoulder arthroplasty (rTSA) is an effective procedure to improve shoulder pain, range of motion, and function for a variety of conditions, including glenohumeral osteoarthritis and rotator cuff arthropathy. However, up to 22% of patients have persistent shoulder pain 12 to 24 months following rTSA, even in the absence of surgical complications. Currently, there are no widely accepted non-pharmacological treatments for persistent postoperative pain after rTSA. This case report details the successful management of a 64-year-old woman with chronic postoperative shoulder pain following rTSA. She was treated with single-lead percutaneous peripheral nerve stimulation to the right axillary nerve for eight weeks with 12 Hz motor-level stimulation. She demonstrated improvement in shoulder flexion active range of motion, shoulder flexion strength, and shoulder abduction strength. Her Shoulder Pain and Disability Index total score improved from 26.93% to 8.46% one year following treatment. She reported an overall Global Rating of Change of +7 one year following treatment. This case's success demonstrates that short term peripheral nerve stimulation may provide long-term improvement of persistent post-operative pain and dysfunction in patients with painful rTSA.

Results of the Simultaneous Combination of Ponatinib and Blinatumomab in Philadelphia Chromosome-Positive ALL.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In this analysis, we update our experience with the chemotherapy-free regimen of blinatumomab and ponatinib in 60 patients with newly diagnosed Philadelphia chromosome (Ph)-positive ALL. At a median follow-up of 24 months, the complete molecular response rate by reverse transcriptase-polymerase chain reaction was 83% (67% at the end of course one), and the rate of measurable residual disease negativity by next-generation clono-sequencing was 98% (45% at the end of course one). Only two patients underwent hematopoietic stem cell transplantation (HSCT). Seven patients relapsed: two with systemic disease, four with isolated CNS relapse, and one with extramedullary Ph-negative, CRLF2-positive pre-B ALL. The estimated 3-year overall survival rate was 91% and event-free survival rate was 77%. Three patients discontinued blinatumomab because of adverse events (related, n = 1; unrelated, n = 2) and nine discontinued ponatinib because of cerebrovascular ischemia, coronary artery stenosis, persistent rash, elevated liver function tests with drug-induced fatty liver, atrial thrombus, severe arterial occlusive disease of lower extremities, pleuro-pericardial effusion, and debilitation. In conclusion, the simultaneous combination of ponatinib and blinatumomab is a highly effective and relatively safe nonchemotherapy regimen. This regimen also reduces the need for intensive chemotherapy and HSCT in first remission in the majority of patients.

Rare insights: Atypical MRI features of juvenile SLE.

Patients with systemic lupus erythematosus (SLE) frequently show symptoms of central nervous system involvement, termed neuropsychiatric SLE (NPSLE). Central nervous system (CNS) vasculitis is one of the neurological pathologies seen in CNS lupus. Patients with NPSLE typically present with nonspecific symptoms such as headache and cognitive impairment. Due to a lack of specific neuroradiological findings, diagnosis and management of such patients remain a big challenge. We report a 5-year-old girl who presented with fever and headache as the only neurological symptoms. Magnetic resonance imaging (MRI) of the brain showed focal grey and white matter lesions, suggestive of inflammatory or demyelinating ethology. Even though MR imaging findings may not be diagnostic of CNS lupus vasculitis, the study is routinely performed as a part of initial evaluation in patients with juvenile SLE showing neurological signs and symptoms.