bluuebunny/crossref_metadata_2025 huggingface dataset:
Maximal androgen blockade therapy (MAB) for prostate cancer (PC) and risk of bone fractures: A systematic literature review and meta-analysis.
Authors: Turco Fabio , Saporita Isabella , Calabrese Mariangela , Carfi Federica Maria , Mogavero Andrea , Treglia Giorgio , Gillessen Silke , Di Maio Massimo , Tucci Marcello , ButtIgliero Consuelo , Vogl Ursula
Published: June 2024

e17111

Background: Androgen deprivation therapy (ADT) increases the risk of fractures. The addition of an androgen receptor pathway inhibitor (ARPI) to ADT (MAB) has shown to improve outcomes compared to ADT monotherapy in patients (pts) with metastatic castration-resistant PC (mCRPC), non-mCRPC (nmCRPC), metastatic hormone-sensitive PC (mHSPC), high-risk localized disease and high-risk biochemical relapse. There is no definitive evidence whether MAB increases the risk of fractures compared to ADT alone. Methods: We conducted a systematic review of all clinical trials assessing treatment with an ARPI plus ADT for pts with PC having placebo plus ADT as control arm, using the PubMed/Medline and Cochrane library databases. We also performed a meta-analysis to compare the risk of fractures of each ARPI versus placebo. Further we assessed the number of pts receiving bone protecting agents (BPA) in the studies selected. The comparison between ARPI and placebo in terms of risk of fractures was performed using odds ratio (OR) as meta-analytic outcome. Results: We identified 15 studies comprising 15183 pts (8638 treated with an ARPI and 6545 with placebo), of which 3 studies evaluated abiraterone, 3 apalutamide, 3 darolutamide and 6 enzalutamide. Each ARPI resulted in a statistically significant increase in the risk of fractures compared to placebo (see table), but without statistical differences among the different ARPIs since there is an overlap between the confidence intervals (CI) of the pooled outcome measure of different ARPIs compared to placebo. Only 7/15 studies reported the number (n°) of pts treated with a BPA of which 4 were in mCRPC, 2 in nmCRPC and one in the mHSPC setting. The highest percentage was found in studies including mCRPC pts, of which 35-50% received a BPA. In the studies in the nmCRPC setting, 10-11% of pts received a BPA while in the only mHSPC study reporting data on the use of BPA only two pts (0.4%) in the ARPI group received BPA and no patient in the placebo group. Conclusions: In our meta-analysis MAB resulted in a statistically significant increase in fracture risk compared to ADT regardless of the ARPI used. Data on the use of BPA should be properly reported in future clinical trials. Since long term MAB represents the standard of care in various settings of PC, the use of a BPA should be generally recommended. Dosing and frequency of BPA needs to be adapted according to the specific PC setting. [Table: see text]
Rate of p53 and MMR IHC assessment accordance between matched D&C and hysterectomy samples in uterine cancer.
Authors: Syrios John , Christidis Anastasios , Tziortziotis Dimitrios , Sourla Antigoni , Mazis Kourakos Dimitrios , Vlachos Dimitrios , Vlachos Georgios , Mitsakos Barbayiannis Kyriakos
Published: June 2024

e17587

Background: International guidelines strongly suggest assessment of POLe, MMR, p53 in patients with early stage endometrial cancer. MMR and p53 are commonly assessed with IHC after hysterectomy (+/-BSO). The fixation procedure and the high tumor cellularity of D&C specimens may permit accurate p53 and MMR evaluation. Early knowledge of p53 and MMR status in D&C samples may drive surgical treatment modalities and fertility sparing decision. Methods: In this single center study 73 matched D&C and hysterectomy samples in patients with clinically early stage endometrial cancer were collected and p53 and MMR status was assessed with IHC.Samples were obtained by gynaecologists and gynaecological oncologists and independently assessed by two expert in gynaecological oncology pathologists at REA hospital (Athens-Greece).Immunohistochemistry was performed using Ventana Benchmark Ultra. To determine MMR status, sections were scored visually for loss or intact expression of the proteins MSH6, MSH2, MLH1 and PMS2. Interpretation of immunostaining for each protein was classified as: (i) “retained,” when ≥10% of tumor cells showed a moderate to strong expression; (ii) “loss,” when no evidence of nuclear expression was seen in cancer cells; (iii) “indeterminate,” if IHC staining in tumor cells was less intense compared to the internal control or expression was retained in <10% of neoplastic cells.If, however, the presence of “indeterminate” immunostaining in one or more proteins was coupled with a convincing loss of expression in at least one protein, the tumor was interpreted as “dMMR” tumor.The study was carried out within January 1st -December 1st 2023. Results: There was a 100% accordance between p53 assessment in all 73 matched D&C and hysterectomy specimens. Discrepancy in MMR result was observed only in 1 out of the 73 cases, which stained negative for MLH1 in D&C but positive in hysterectomy, yielding an accordance of 98,96% between D&C and hysterectomy specimens. Conclusions: p53 & MMR status can be accurately assessed with IHC in D&C samples. Repeat assessment after hysterectomy may not be necessary. Early knowledge of the molecular imprint of the disease on D&C samples may drive treatment decisions regarding surgical procedures, fertility preservation and further treatment plans. [Table: see text]
Pole mutated endometrial carcinoma: Clinical and genomic characteristics from a real-world UK cohort.
Authors: Chaabouni Narda , Vroobel Katherine , Attygalle Ayoma , Proszek Paula , Johnson Liam , Smalley Michaela , Shaikh Ridwan , Lalondrelle Susan , Taylor Alexandra , George Angela Joy
Published: June 2024

e17600

Background: Pathogenic mutations within the DNA polymerase epsilon (POLE) exonuclease domain characterise the POLE/ultra-mutated molecular subgroup as defined by the Cancer Genome Atlas (TCGA) Research Network. Our study aimed to evaluate clinical and genomic characteristics of POLE mutated endometrial carcinoma (EC) from a real-world cohort. Methods: 246 tumour samples from patients diagnosed with primary endometrial cancer (EC) between September 2007 and June 2022 were sequenced using the Royal Marsden RMH200 Solid panel which includes 233 genes and evaluates microsatellite instability (MSI) and tumour mutational burden (TMB). Droplet Digital PCR (ddPCR) was used for MLH1 promoter methylation status in each case. Mismatch repair proteins (MMR) and P53 were tested by immunohistochemistry (IHC). Patients’ characteristics were documented from our electronic records. Results: POLE mutations were identified in 21 patients (8.5%). Mean age at diagnosis was 63 years old (52-92). Mean BMI was 28.5 (21.1-48) and 38.1% of patients had hypertension (n=8). 20 cases were stage I (95%) and 1 case was stage III (5%). Predominant histological subtype was endometrioid in 17 cases (81%). The other histological subtypes comprised clear cell (n=1), mixed (n=1) and carcinosarcoma (n=2). All patients had surgery and 15 (71.4%) received adjuvant therapy which included chemotherapy in 4 (19%) cases. Mean TMB was 125.11 mut/Mb (25.77-345.82). 8 (38%) cases demonstrated MMR deficiency with MLH1 promoter hypermethylation detected in 7/8 cases. P53 was wild type (WT) in 17 (81%) and subclonal mutant in 4 (19%) of cases. 13 (61.9%) cases were microsatellite stable and 8 (38.1%) MSI-high. Recognised pathogenic POLE variants were identified in 16 (76.2%) cases: V411L* c.1231G (n=7), P286R c.857C>G (n=4), A456P c.1366G>C (n=2), A465V c.1394C>T (n=1), P436R c.1307C>G (n=1), M444K c.1331T>A (n=1).After a median follow-up of 21 months, one patient developed distant recurrence and died of progressive brain metastases following surgery for stage IA grade 1 endometrioid carcinoma, however recurrence was not biopsied. Conclusions: In this real-world cohort, POLE mutated EC cases were associated with a favourable prognosis. One distant recurrence was observed in initially uterine-confined case but was not histologically proven. Further research is needed to prognosticate POLE mutated EC and define appropriate adjuvant treatment recommendation.
Recurrent vulvar squamous cell carcinoma: Outcomes across the treatment spectrum—Are we making progress?
Authors: Meloche Claudia , Dinh Trish , Spaans Johanna , Zhang Tinghua , Weberpals Johanne I
Published: June 2024

e17603

Background: No standard treatment exists for recurrent vulvar squamous cell carcinoma (VSCC) and the prognosis is poor. This retrospective study reports on outcomes of recurrent and progressive VSCC patients (pts) across various treatments. Methods: This was a single-center retrospective cohort study conducted at the Ottawa Hospital (Ottawa, Canada). Pts with histologically proven VSCC treated between 2000-2023 were identified, and the study population comprised pts who either recurred or progressed after/during first-line therapy. Clinicopathologic data were collected, and descriptive statistics were performed according to pt demographics, tumor characteristics and treatment modality. Median progression free survival (PFS) and overall survival (OS) were determined by treatment type. The outcomes of unique cases treated with novel therapies are also highlighted. Results: There were 311 pts with a diagnosis of VSCC. Ninety-five pts with recurrent/progressive disease formed the study population with a median age of 72 years and 52% having at least stage III disease at initial diagnosis according to FIGO 2021 staging. The prevailing treatment at time of diagnosis was surgery (74%), with 40% of pts also undergoing radiation, chemotherapy, or a combination of both. Location of disease progression or recurrence was regional 53 (56%), inguinal 31 (33%) and distant 11(12%). There were 60 pts (63)% who had one recurrence, as well as 18 pts (19%) and 3 pts (3%) with two and three recurrences, respectively. Of all patients, 14/95 (15%) showed evidence of early progression following treatment. Treatment for first recurrence included: radiation (18.9%), surgery (16.8%), no treatment (16.8%), chemotherapy (11.6%), chemoradiation (9.4%), surgery with radiation (7.3%) surgery and chemoradiation (2.1%), surgery and chemotherapy (1.1%), and investigational therapy (1.1%). The most common chemotherapy regimen used was cisplatin, while the predominant surgical procedure performed was radical vulvectomy. Two pts received Pembrolizumab for treatment of recurrent disease. One pt received a combination of carboplatinum, paclitaxel and bevacizumab followed by maintenance pembrolizumab for 55 cycles (PFS 27.1 months, mo). A second pt was treated for a second recurrence with carbo-taxol followed by single agent pembrolizumab for 27 cycles with stable disease (PFS 15.7 mo). The mPFS after treatment of first recurrence was 11.6 mo for surgery, 8.7 mo for radiation, 8 mo for chemotherapy, 3.2 mo for chemoradiation, and 2.2 mo for no treatment. Among VSCC pts with recurrent or progressive disease, the median OS from all causes was 21 mo. Conclusions: Pts with recurrent/progressive VSCC who underwent surgery had the most favorable outcomes. Significant promise was shown with pembrolizumab and highlights the need for immunotherapy clinical trials for this rare and fatal woman’s cancer.
A random forest model to predict the efficacy of KL-A167 in previously treated recurrent or metastatic nasopharyngeal carcinoma based on the data from the KL167-II-05-CTP study.
Authors: Fan Guangyu , Xie Tongji , Tang Le , Gui Lin , Shi Yuankai
Published: June 2024

e18012

Background: KL-A167 is a fully humanized monoclonal antibody targeting programmed cell death-ligand 1. KL167-Ⅱ-05-CTP study had evaluated the efficacy and safety of KL-A167 in Chinese patients with previously treated recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). The results of KL167-Ⅱ-05-CTP study showed that not all patients with R/M NPC could benefit from KL-A167 therapy, and an effective model to predict the efficacy of KL-A167 is necessary. Methods: The baseline data of clinical characteristics, laboratory examination and imaging of patients with R/M NPC in KL167-Ⅱ-05-CTP study were collected, who received KL-A167 therapy. The progression-free survival (PFS) was selected as the predicted variable. Patients were randomly divided into training cohort (70%) and test cohort (30%). In the training cohort, uni-Cox regression was used to estimate the value in predicting PFS, and least absolute shrinkage and selection operator (LASSO)-Cox regression was performed to screen clinical, laboratory and imaging indexes to build random forest model. The accuracy of this random forest model was validated in the test cohort. Results: In this study, 137 patients with R/M NPC were enrolled, and the median PFS of them was 2.689 (95% confidence interval [ CI]: 1.475-4.098) months. A total of 14 indexes with P < 0.05 were selected to perform LASSO-Cox regression, and 10 indexes (blood lactate dehydrogenase, blood creatinine, left ventricular ejection fraction, body temperature, weight, blood lymphocyte count, blood chloride ion concentration, Eastern Cooperative Oncology Group performance status, blood triglyceride and blood alanine aminotransferase) were used to build prediction model. The C-index of risk score from this model was 0.820 and 0.790 in the training and test cohort, respectively. Patients were divided into the high and low risk groups according to the median risk score, and the median PFS of the high risk group was shorter than that of the low risk group (training cohort: 1.377 vs. 4.197 months, P < 0.001, hazard ratio [ HR] = 1.142, 95% CI: 1.111-1.175; test cohort: 3.475 vs. 10.984 months, P < 0.001, HR = 1.100, 95% CI: 1.060-1.142). Conclusions: In this study, a random forest model based on 10 clinical, laboratory and imaging indexes was constructed and showed a potential value in predicting the PFS of KL-A167 therapy in Chinese patients with previously treated R/M NPC, which could help to guide clinical trials and practices.
Time restricted eating (TRE) and immunotherapy outcomes in head and neck squamous cell carcinoma (HNSCC) via modulation of microbial butyrate and tryptophan metabolic pathways.
Authors: Bari Shahla , Eysha Mostafa , Alhomsi Muhammad , Hathout Mahmoud , Patel Krupal , Li Lucas , Sarfraz Humaira , Conejo-Garcia Jose , Muzaffar Jameel
Published: June 2024

e18028

Background: Metastatic HNSCC continues to have very poor prognosis. Only a fraction of patients respond to immune checkpoint blocker therapy (ICB), with no effective treatment options for non-responders. Gut microbial composition and diversity have been associated with response to ICB in many cancers including HNSCC. We have previously demonstrated that TRE significantly improved progression free survival via modulation of gut microbiota. We herein report our mechanistic data demonstrating critical role of microbially mediated butyric and tryptophan metabolic pathways in augmenting antitumor immune response to ICB. Methods: Paired blood and stool samples, at baseline and at first response assessment, from 43 HNSCC patients enrolled in the TRE study (NCT05083416) was collected and analyzed using untargeted and targeted metabolomics, focusing on tryptophan and short chain fatty acid pathway. Further shot gun metagenomic sequencing was conducted on stool samples. Finally, we performed an in vitro luciferase cytotoxicity assay using SCC-4 human cancer cells to demonstrate TRE mediated antitumor immune response. We co-cultured MHC-I and NY-ESO-1, and NY-ESO-1-specific TCR-transduced T cells. tumor cells and the T cells under different conditions of butyrate concentration and T cell-to-tumor cell ratio (1:5, 1:10) and evaluated T cell mediated tumors killing. Results: We noted significantly higher abundance of clostridium butyricum (OR-1004, p-0.0002) with corresponding higher expression of butyrate kinase enzyme in stool of patients who observed TRE (OR-1.9, p-0.0003) vs those who did not, leading to higher concentration of fecal butyric acid and hydroxy indole acetic acid (HIAA) (OR-4.2, p-0.003), both of which were independently associated with longer progression free survival (HR-0.9, p<0.01). Higher abundance of butyric acid in gut is known to enhance the gut barrier function with consequent decrease in plasma butyrate and HIAA, lower systemic levels of which, was found to be associated with longer progression free survival in our cohort (OR-0.9, p-0.05). Both butyrate and 5HIAA are known activators of immunosuppressive aryl hydrocarbon receptor (AhR) expressed on cytotoxic CD8T cells, inhibiting CD8 mediated antitumor response. In line with our hypothesis, we observed that butyrate and 5HIAA impaired CD8 T mediated T cell killing of tumor cells in a dose-dependent manner. Conclusions: These results suggest that TRE favorably modulates ICB response via enrichment of gut microbiota with butyrate producing microbial organism, leading to increased abundance of gut butyrate and microbial tryptophan metabolites and their consequent reduction in systemic circulation, ultimately enhancing antitumor immune response.
Immune system evaluation in a cohort of Brazilian patients with head and neck squamous cell carcinoma who are non-smokers and alcoholic beverages abstainers.
Authors: Castro Gilberto , Lepique Ana Paula , Cruz Lorraynne Letycia Prado , Pasini Fatima Solange , Maistro Simone , Roela Rosimeire Aparecida , Katayama Maria Lucia Hirata , Ribeiro Ana Carolina Prado , dos Santos Alexandre Bezerra , Koike Folgueira Maria A. A. , Kowalski Luiz Paulo
Published: June 2024

e18030

Background: Smoking and alcohol abuse are the main risk factors for head and neck squamous cell carcinoma. However, some patients do not present clear risk factors. We are studying a cohort of Brazilian patients that are non-smokers and alcoholic beverage abstainers. Brazilian people have peculiar ethnic characteristics, reflecting a miscegenation of Europeans, Africans and Amerindians. There is evidence that ethnic background may influence germline and somatic mutations, as well as tumor behavior. One of the aims is to evaluate the immune system of this cohort of miscegenated head and neck squamous cell carcinoma patients who are non-smokers and alcoholic beverages abstainers. Methods: In this prospective study, until now we have included 16 patients: 10 women and 6 men, who were non-smokers and alcoholic abstainers. All patients answered a questionnaire and collected blood, saliva and tumor samples before treatment for analysis. Self-declared skin color was mainly brown (n=8,) followed by white (n=6), black (n=1) and yellow (n=1). The median age was 56.5 years. Patients were diagnosed with oral (n=10), glotic (n=1), oropharyngeal (N=1,) lip and gingiva (n=4) carcinoma; clinical stages I (n=3), II (n=6); III (n=1) and IVA (n=5). Fourteen patients were already operated on. Results: Peripheral blood analysis revealed that within the mononuclear cell population CD16+CD66b-HLA-DR- cells, possibly NK, were significantly more frequent in patients with cancer stage III and IVA, than in patients with cancer stages I and II. There was also a significant negative correlation between the frequency of CD16+ cells in the mononuclear population and age of the patients. Finally, we observed that in the granulocyte population, patients with lesion grade I and II have 20-fold more CD16+CD66b+PD-L1+ cells than patients with lesions grade III and IV. It is possible that an IFN gamma driven response may be, in part, responsible for the induction of PD-L1 expression in granulocytes. This hypothesis is corroborated by the positive correlation between PD-L1 expression level in the granulocyte population and the frequency of CD16+CD66b- population (p=0.01, Pearson correlation 0.62). No other parameter, which included lymphocytes T and B, and monocytes, displayed correlation with clinical data. Conclusions: Our results suggest NK and myeloid cell frequency may vary in our cohort according to lesion grade as a consequence of immune responses. However, these are preliminary results, and other parameters acquisition, as well as a larger sample, will be needed for definitive conclusions.
Treatment of iodine refractory well differentiated thyroid carcinoma: Real world data from a tertiary center in Mexico.
Authors: Cervin Cristhel , Sánchez Valencia Patricia Elvira , Del Valle Delgado Karina , Cardenas Eduardo , Cervantes Guadalupe
Published: June 2024

e18064

Background: Sorafenib and lenvatinib are the only drugs approved based on phase III clinical trials as first-line treatment in radiation-refractory, progressive, differentiated thyroid carcinoma, with limited data available for a direct comparison of these tyrosine kinase inhibitors. We aimed to evaluate the progression-free survival between the two groups treated with both medications in a Mexican tertiary center. Methods: In this retrospective study conducted from December 2015 to June 2024, we evaluated the outcomes of 38 patients with metastatic/locally advanced, progressive, RAI-refractory DTC/PDTC, treated with sorafenib or lenvatinib. The primary outcome was the probability of progression-free survival (PFS) between both groups. Results: Eighteen patients treated with sorafenib and twenty patients with lenvatinib were included. The median age was 64.5 years, and 76% were women. Papillary histology was the most frequent (81%), and they were diagnosed at stage IV in the majority of cases (82%). More than half of the patients had previously undergone surgery, radiotherapy, and/or radioactive iodine treatment. After a median follow-up of 13.2 months, no difference in PFS was observed between the sorafenib and lenvatinib arms (HR 1.53, 95% CI 0.38-6.05, p=0.54). Conclusions: Sorafenib and lenvatinib have shown comparable efficacy in prolonging progression-free survival in Mexican patients with metastatic/locally advanced, progressive, RAI-refractory DTC/PDTC, leading to markedly superior outcomes compared to pivotal studies.
Efficacy and safety of selpercatinib in advanced RET-altered thyroid cancers: A meta-analysis and systematic review.
Authors: Muhibullah - , Shafique Nouman , Kaur Navneet , Ahmed Jawad , Zain Sarmad , Naqvi Syed Mujtaba Ali , Bajwa Shammas , Nawaz Hassan , Ur Rehman Atta , Haider Ali , Ghaffar Ali , Javeed Zainab , Iqbal Abdul Ghani , Ehsan Amna , Khanal Prajjwal , Shafique Adeena , Shafiq Iqra , Kumar Besham , Hussain Rida , Rizwan Umer
Published: June 2024

e18073

Background: Selpercatinib is a highly selective RET inhibitor that is used for the treatment of RET-mutant medullary thyroid cancers, but its efficacy and safety is not fully understood. Our objective is to summarize available literature on the safety and efficacy profile of Selpercatinib. Methods: A search was conducted on PubMed, Embase and Cochrane from foundation to 31st January 2024. Patients aged above 18 with Advanced RET-Altered Medullary Thyroid Cancers who received Selpercatinib were identified. Data abstraction was done based on objective response rate, complete response rate, any grade adverse effect (AE) and grade ≥3 AE. Analysis was done using R (v.4.3) and reported as proportions with respective 95% confidence intervals (CI) on forest plots. Results: Four studies were identified that reported the use of Selpercatinib in Advanced RET-Altered Medullary Thyroid Cancers. Our analysis showed that the pooled proportion of objective response rate and complete response rate was 74.8% (95% CI: 70.1% – 79%) and 4.9% (95% CI: 3.1% – 7.7%) respectively. Pooled proportion of patients experiencing any grade AE and grade ≥3 AE was 93.4% (95% CI: 90.4% – 95.6%) and 46.2% (95% CI: 41.1% – 51.3%) respectively. Conclusions: Selpercatinib is a novel RET inhibitor which has potential use against RET-Altered Thyroid Cancers. It has an overall acceptable safety and efficacy profile. However it requires further studies to establish its adverse effects and clinical application. [Table: see text]
Timing of allogeneic hematopoietic cell transplantation for myelofibrosis and other myeloproliferative neoplasms.
Authors: Mercer Joshua S. , Bradbury Claire I. , Thomas Samantha M. , Ramalingam Sendhilnathan , Gasparetto Cristina , Choi Taewoong , Sung Anthony D. , Sarantopoulos Stefanie , Long Gwynn Douglas , Alyea Edwin , Horwitz Mitchell E. , Chao Nelson Jen An , Hong Sanghee
Published: June 2024

e18517

Background: Myeloproliferative neoplasms (MPN) and myelodysplastic syndrome (MDS)/MPN overlap syndromes are rare hematopoietic malignancies in which allogeneic hematopoietic cell transplantation (HCT) is the only treatment with curative potential. Even for higher risk patients, the optimal timing for HCT is largely unknown. We interrogated HCT outcomes of myelofibrosis (MF) and the rest of MPN, MDS/MPN overlap based on the timing of HCT from diagnosis (Dx) to help oncologists determine the optimal timing to refer patients for HCT. Methods: This retrospective, single-center study obtained data from our HCT database. We included adult (>18 years; y) patients who received their first allogeneic HCT between 2015 and 2022 for initial Dx of MPN or MDS/MPN overlap. We included all donor types and graft sources. Analysis was separated by MF vs. others (other MPN and MDS/MPN) to account for fibrotic vs proliferative nature of disease progression and sample size. The primary variable was the time from Dx to HCT. The primary endpoint was overall survival (OS) from HCT. Secondary endpoints were progression free survival (PFS) and non-relapse mortality (NRM) from HCT. Results: 46 patients (n=27 for MF, n=19 for others) were included. 59% were male (56% for MF, 63% for others). The median age at HCT for MF was 57y (range 45-72) and for others was 63y (32-75). For patients with MF and others, 85% and 84% received myeloablative conditioning, respectively. In the MF group, all patients had PBSC grafts and 37% of grafts were from match-related donors; in the others group, 89% had PBSC grafts (11% had BM grafts) and 53% of grafts were from match-related donors. The median time from Dx to HCT for patients with MF was 28 months (m; range 4-166) and for others was 11m (2-423). In the MF group, those whose HCT <1y from Dx had improved OS (Table) and PFS (1y, 83.3% vs. 53.3%, p=0.031) compared to HCT ≥1y after Dx. However, no differences were found in OS or PFS for <6m vs. >6m from Dx to HCT. No differences in OS/PFS were seen based on the timing of HCT in the others group. Conclusions: Patients with MF, but not with other MPN or MDS/MPN, who received allogenic HCT <1y from Dx had significantly improved OS and PFS. Our results suggest that early referral to HCT after confirmation of marrow fibrosis for higher risk MF may influence HCT outcomes positively. However, lack of improvement in OS/PFS at 6m suggests that addressing individual risks and initiating appropriate therapies for MF first may more effectively balance risks of post-HCT complication with disease progression. Additional studies investigating timing of HCT will help oncologists to direct management of MPN and MDS/MPN overlap. [Table: see text]
Relationship of body mass index and plasma imatinib levels in CML patients and mitigation of clinical impact using PK-guided dosing strategy.
Authors: Maroselli Paul , Fanciullino Raphaelle , Colle Julien , Farnault Laure , Rocher Pauline , Venton Geoffroy , Costello Régis , Ciccolini Joseph
Published: June 2024

e18522

Background: Imatinib is a mainstay of treatment for patients with chronic myeloid lymphoma (CML). Exposure-response relationships have been demonstrated and trough levels between 800 and 1000 ng/ml are usually associated with Major Molecular Response (MMR), prolonged survival and acceptable safety. The extent to which body mass index (BMI) might influence drug pharmacokinetics (PK) and clinical outcome remains to be investigated. Methods: Therapeutic drug monitoring was performed in 60 adult patients (56 years, M33/27F) starting imatinib (400 mg QD) for CML, and baseline deviation from target Cmin was used to subsequently adjust dosing using Monolix software. Baseline BMI was calculated and collected along with other patient characteristics and comedications likely to alter imatinib PK. Response (MMR at 3 months) and drug-related toxicity (CTCAE grading) were recorded. Patients were divided into three subgroups: BMI<18.5; 18.5<BMI<24.5, and BMI>24.5. The association between BMI and trough imatinib levels at baseline, further differences in toxic events and response rate between cohorts, as well as differences in dosing after PK-guided dose adjustment, were all tested using appropriate statistical analysis. Results: Mean imatinib trough levels at baseline were 1172 (754-4737), 870 (276-1767) and 820 (334-2217) ng/ml for patients with BMI<18.5, 18.5<BMI<24.5 and BMI>24.5, respectively. Patients with BMI<18.5 were statistically overexposed (p<0.01, ANOVA). Conversely, there was a trend towards lower exposure in patients with BMI>24.5, but this was not statistically significant. Multivariate analysis confirmed that low BMI was an independent factor for overexposure with imatinib. After PK-guided dosing, a statistically significant difference in dosing after correction was observed, as overexposed patients had their dose reduced to an average of 330 mg QD, whereas underexposed patients had their dose increased to an average of 500 mg QD (p<0.01, paired t-test). Consequently, when comparing in the three different cohorts the incidence of both response and toxic events, no difference was observed among patients (p=0.33 and p=0.911 for efficacy and toxicity respectively, Chi-2 test). Conclusions: Low BMI (<18.5) puts patients at risk of significant overexposure to imatinib, whereas there is a trend towards lower exposure in patients with high BMI (>24.5). This could potentially lead to either increased toxicity or lack of efficacy is no adjustment in dosing is performed. Here, TDM with subsequent adaptive dosing helps to correct the dose according to the initial deviation from target, thus smoothing the clinical impact of the differences in exposure observed at the start of treatment.
Dasatinib versus high-dose imatinib for chronic-phase chronic myeloid leukemia: A meta-analysis of randomized control trials.
Authors: Zafar Fabeha , Shivakumar Divya , Wankhade Diptish , Poombal Dr. , Winayak Rahul , Malik Ghulam Mustafa Ali , Mahapatra Shruti Sagar , G.C. Shasan , Ashraf Laraib , Huynh Truc , Mylavarapu Maneeth , Haider Ali
Published: June 2024

e18523

Background: Chronic Myeloid Leukemia (CML) is one of the few cancers with a unique and identifiable genetic mutation. The issue of imatinib resistance is becoming increasingly significant in patients with chronic phase chronic myeloid leukemia (CP-CML). Methods: We systematically searched Pubmed/MEDLINE, EMBASE, and Cochrane Library from inception through March 2023 to analyze the published literature of randomized control trials (RCT) regarding patients with CP-CML resistant to imatinib. The review was carried out according to the PRISMA guidelines, and the review protocol was registered at PROSPERO (CRD42023422749). The screening was done to include studies with the following criteria: 1) Randomized control trials; (2) comparisons between high-dose imatinib and dasatinib; (3) patients with imatinib-resistant CP-CML; and (4) measurements of Major Molecular Response (MMR) and Complete Cytogenetic Response (CCyR). The quality assessment of the included studies was carried out using JBI's (Joanna Briggs Institute's) RCT checklist. Risk ratios were used to compare the effects of dasatinib vs high dose imatinib with respect to outcomes on MMR and CCyR. Data was analyzed using R version 6.2.1. A p-value of <0.05 was considered statistically significant. Results: We included three studies totaling 929 patients. 585 (62.9%) patients were males. There is a statistically significant improvement in MMR (RR 1.71, 95% CI 1.09 to 2.69, p=0.021, I. = 52%) and an increase in the likelihood of achieving a CCyR (RR 1.24, 95% CI 0.90 to 1.71, p=0.197, I. =74%). Conclusions: Dasatinib shows potential as a management in CP-CML patients with imatinib resistance. However, these results should be interpreted cautiously, and further validation needs to be done with high-quality, large-scale cohort studies or clinical trials to address the safety of dasatinib.
Myelofibrosis prognostic models validated in an underserved minority population: A retrospective analysis.
Authors: Kamel Josette Mary , Yan John , Goldfinger Mendel , Feldman Eric J. , Konopleva Marina , Mantzaris Ioannis , Shastri Aditi , Kornblum Noah , Gritsman Kira , Sica Alejandro R. , Shah Nishi , Cooper Dennis , Verma Amit , Goel Swati
Published: June 2024

e18529

Background: Contemporary prognostic models for myelofibrosis (MF) risk stratify patients using a heterogeneous composition of clinical and genetic factors. Little is known regarding how these scores perform in underserved populations. Our study assesses how well current models stratify risk at an inner-city tertiary care center which carries unique challenges including increased diversity, later disease presentation, and less access to healthcare resources. Methods: We retrospectively reviewed 88 MF patients referred to our center in the Bronx, NY between 2000 and 2023. Clinical and genetic data were used to calculate prognostic scoring for DIPSS, DIPSS plus, MIPSS70, MIPSSV2, and GIPSS. Overall survival (OS) was calculated from the time of diagnosis and non-deceased patients were censored at last follow-up. Patients with missing clinical or genetic data were excluded from individual analysis. Models were assessed via univariate and multivariate cox proportional hazards analysis followed by concordance analysis. Results: Mean age of the cohort was 66 years (range 29-88) with median survival of 7.7 years. Ethnicities included non-hispanic white (NHW) [30 (34.1%)], NH black [23 (26.1%)], NH asian [6 (6.8%)], and hispanics of all races [22 (25%)] (unknown n=7). DIPSS (n= 88, HR 1.77, CI 1.22 - 2.41, p-value = 0.0001), DIPSS plus (n=83, HR 1.54, 1.15-2.07, p = 0.0033), MIPSS70V2 (n=68, HR 2.06, CI 1.23 - 3.61, p = 0.0088), and GIPSS (n=69, HR 2.73, CI 1.24 - 3.78, p = 0.0063) were significantly associated with OS based on univariate analyses. Both DIPSS and GIPSS were significant even upon adjustment for each other (p=.009 and p=.043 respectively). MIPSS70 (n=73, HR 1.87, CI .93 - 3.88, p = 0.0842) did not meet significance. In terms of predictive accuracy based on C-index scores, DIPSS and GIPSS combined analysis scored highest (0.773), followed by GIPSS (.7226), DIPSS (0.719), MIPSSV2 (0.717), DIPSS Plus (0.6495), then MIPSS70 (0.6414). Conclusions: Our study shows that GIPSS, DIPSS, DIPSS plus, MIPSSV2 all function as valid prognostic models in the inner-city setting and that integrating both clinical and genetic models may have higher predictive value than either individual model alone. Additionally, GIPSS predicted superior survival outcomes to what was observed in our cohort for higher risk categories, prompting the need for further investigation. [Table: see text]
Immunohistochemical markers in the prognostic model for survival of patients with diffuse large B-cell lymphoma.
Authors: Kobilov Odiljon , Kamishov Sergey
Published: June 2024

e19055

Background: Currently, relevant issues include the study of the role of immunohistochemical markers in patients with diffuse large B-cell lymphoma (DLBCL) with extranodal involvement to predict the outcomes of the conducted therapy. Methods: A retrospective study included 81 patients with diffuse large B-cell lymphoma (DLBCL) involving the liver and spleen with extranodal manifestations, who underwent treatment and were under outpatient monitoring in a hospital setting. The average age of the patients was 60.7±7.5 years. The expression of pan-B-cell antigens CD20, CD79A, PAX 5 (monomorphic intense nuclear expression), CD5, CD45, CD30, BCL-2, BCL-6, Ki-67, MUM1, GCET1, FOXP1 was examined in the patients. To exclude the polymorphic blastoid variant of lymphoma with CD5 expression in mantle cells, the study of cyclin D1 expression was conducted. Results: All patients began treatment with R-CHOP chemotherapy. In 37 cases, this regimen had to be replaced with DHAP in 23 (62.2%) patients due to the low effectiveness of the 1st-line chemotherapy, and in 14 (37.8%) after completing the full course (6 cycles) of treatment. Over the 6-year observation period, despite identical treatment, the 5-year survival rate was 60.5%. Among 32 (39.5%) patients, there was a fatal outcome due to the progression of the pathological process during treatment. Moderate expression was characteristic for the markers CD5, CD30, PAX-5, FOXP1, and GCET1, while high expression was observed for CD10, CD45, CD79A, Bcl-6, MUM1, and Ki-67. High expression of Bcl-2, Bcl-6, GCET1, and Ki-67 exceeding 60% is a prognostically unfavorable factor significantly impacting the survival of patients. The most unfavorable outcomes were observed with the combination of Bcl-2 and Ki-67 expression exceeding 60% along with CD-45. The combination of Ki-67 expression exceeding 60%, CD-79, and MUM1 also resulted in an unfavorable outcome in all cases. The prognostic scale, using Cox's proportional hazard, allows predicting the prognosis of diffuse large B-cell lymphoma with extranodal involvement with a probability of 87.2%. Conclusions: In our studies, it has been demonstrated that adverse immunohistochemical characteristics of diffuse large B-cell lymphoma with extranodal involvement include high expression of Bcl-2, Bcl-6, GCET1, and a Ki-67 proliferation index exceeding 60% (p<0.025).
Diagnosis disclosure patterns among patients with plasma cell disorders.
Authors: Malik Maria , Dalvi Akshay , Derkach Andriy , Sahagun Sanchez Aldana Ana M. , Hurtado Martínez Jorge Arturo , Merlo Gia , Ahlstrom Jennifer M. , Hydren Jay R. , Usmani Saad Zafar , Chimonas Susan , Ortiz Robin , Shah Urvi A.
Published: June 2024

e19536

Background: Disclosing or withholding information relating to a precancer or cancer diagnosis – including plasma cell disorders (PCDs) like monoclonal gammopathy, smoldering myeloma, and multiple myeloma – across social networks may impact how patients cope with their diagnosis and prognosis. The purpose of this survey was to investigate diagnosis disclosure patterns among patients with PCDs and identify areas for interventions that effectively utilize social support to navigate cancer diagnoses. Methods: We invited participants with PCDs to answer a 34 question online survey about their diagnosis disclosure patterns and perceptions on the HealthTree Cure Hub between April and December 2024. De-identified aggregated responses were analyzed. Results: A total of 510 participants responded (84% with cancer and 15% with precancer). Almost all (98%) reported sharing their diagnosis (Table 1). The most frequent primary individuals to share with were a spouse, domestic partner, or significant other (60%) and friend (s) (10%). Common reasons that participants chose to share included expecting support (45%), empowering others/spreading awareness (31%), and feeling in control (29%). Most (79%) participants reported that sharing information (with the individual they shared the most with) had a positive impact in their coping, with only 4% reporting a negative effect. Study limitations include selection bias. Conclusions: Patients with PCDs have a variety of motivations for sharing their diagnosis and generally perceive disclosure among their primary social networks to be beneficial to their coping. Oncologists may promote coping by encouraging disclosure. [Table: see text]
FIT-001: A phase 1 clinical trial of the farnesyl transferase inhibitor KO-2806 alone or as part of combination therapy for advanced solid tumors.
Authors: Hanna Glenn J. , Adkins Douglas , Thomas Jacob Stephen , Yang Bruce Justine , Patel Manish R. , Sonpavde Guru P. , Henry Jason Timothy , Bendris Nawal , Zhang Zijing , Mitra Amitava , Gasco Hernandez Amaya , Saunders Andrew , Dale Stephen
Published: June 2024

TPS4607

Background: Farnesyl transferase inhibitors (FTIs) block post-translational modification of RAS and other farnesylated proteins. HRAS-driven tumors are highly sensitive to FTI treatment. Recent clinical trials (NCT03719690, NCT02383927) of the FTI, tipifarnib, in patients with HRAS-mutant ( HRAS-m) head and neck squamous cell carcinoma harboring high variant allele frequency mutations (VAF ≥20%), showed objective response rates of up to 50% and favorable long-term outcomes. KO-2806 is a next-generation FTI that has increased potency and improved pharmacokinetic properties. In preclinical studies, KO-2806 has been shown to: (1) enhance tumor growth inhibition of tyrosine kinase inhibitors, including cabozantinib, in multiple clear cell renal cell carcinoma (ccRCC) cell line- and patient-derived xenograft models; and (2) enhance activity of KRAS inhibitors, including adagrasib, in KRAS mutant non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC) mouse models. These preclinical data support clinical investigation of KO-2806 alone and in combination therapy. Methods: FIT-001 is a first-in-human, multicenter, open-label clinical trial that will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics (Pd), and preliminary antitumor activity of KO-2806 as monotherapy or in combination therapy in advanced solid tumors (KO-2806-001; NCT06026410). Up to 270 patients will be enrolled in phase 1a and phase 1b combined across 50 sites. Phase 1a will have separate monotherapy and combination dose-escalation arms. As monotherapy, the study will enroll patients with N/K/HRAS alterations in specific solid tumor types, such as NSCLC, CRC, and PDAC, who are refractory to standard-of-care therapies. KO-2806 and cabozantinib will be combined in patients with advanced or metastatic ccRCC who progressed on ≥1 prior line of immunotherapy-based systemic therapy; KO-2806 and adagrasib will be combined in patients with KRAS-G12C mutant locally advanced or metastatic NSCLC who received ≥1 prior systemic therapy. On the basis of emerging data from phase 1a, two Pd cohorts (n≤12) with mandatory pre- and on-treatment tumor biopsies may be enrolled. In each Phase 1b dose expansion, patients will receive the recommended phase 2 dose [RP2D] of KO-2806 with cabozantinib (in ccRCC) or adagrasib (in NSCLC), or will be randomized by dose if 2 potential KO-2806 RP2Ds are identified for a combination. Other combination arms may also be considered. The study began accrual in October 2023. Clinical trial information: NCT06026410 .
SECuRE: A dose escalation/expansion study to assess the anti-tumor efficacy of 67Cu-SAR-bisPSMA in patients with metastatic castrate resistant prostate cancer.
Authors: Johnson Geoffrey , Lengyelova Eva , Nordquist Luke , Prasad Vikas , Anderson Monique , Gervasio Othon , Parker Michelle , Miller Robert M. , Sartor A. Oliver , Tagawa Scott T.
Published: June 2024

TPS5116

Background: Prostate cancer (PC) is common and despite recent advances in treatment options, patients with metastatic disease still have poor outcomes, warranting the development of new effective therapies in this setting. Prostate-specific membrane antigen (PSMA) is expressed in benign and malignant prostate tissues and luminal surface of salivary/lacrimal glands, small intestine and renal tubules. The double PSMA binding moiety of SAR-bisPSMA in 64Cu-SAR-bisPSMA (imaging) and 67Cu-SAR-bisPSMA (therapy) may offer advantages compared to currently used single-target PSMA agents. Clinical evidence demonstrated 2-3 times higher uptake of 64Cu-SAR-bisPSMA compared to the single-target PSMA agent, 68Ga-PSMA-11. Pre-clinical efficacy data of 67Cu-SAR-bisPSMA in mice showed statistically significant tumor growth inhibition compared to the control group as well as a dose-dependent delay in eventual tumor regression in a PC xenograft study. These results led to the development of this clinical study, which aims to assess safety and anti-tumor efficacy of 67Cu-SAR-bisPSMA in patients with metastatic castrate resistant PC (mCRPC). Methods: SECuRE is a phase I/IIa multi-center, open-label, non-randomized, dose-escalation and cohort expansion study of 64Cu-SAR-bisPSMA and 67Cu-SAR-bisPSMA (NCT04868604). mCRPC patients with progression, prior exposure to at least one androgen receptor pathway inhibitor, and positive 64Cu-SAR-bisPSMA PET may be treated with 67Cu-SAR-bisPSMA. This study is being conducted in 3 phases: a 64Cu-SAR-bisPSMA Dosimetry Phase (n=6), a 67Cu-SAR-bisPSMA Dose Escalation Phase (n=up to 24), and a 67Cu-SAR-bisPSMA Cohort Expansion Phase (n=14). The primary and key secondary objectives include assessment of 64Cu- and 67Cu-SAR-bisPSMA safety and dosimetry, determining the maximum tolerated dose (MTD) or maximum feasible dose (MFD) and anti-tumor efficacy of 67Cu-SAR-bisPSMA. The 67Cu-SAR-bisPSMA dose levels investigated in the escalation phase include: 4 GBq (cohort 1, single dose), 8 GBq (cohort 2, single dose), 12 GBq (cohort 3, single dose) and up to 24 GBq across two doses (cohort 4, two doses at MTD or MFD). The Dose Expansion Phase of the study will allow the administration of up to 4 doses of 67Cu-SAR-bisPSMA at the MTD/MFD. Response measurements include reduction in PSA levels, radiological progression-free survival, duration of response and overall survival. Radiological response will be assessed by RECIST V1.1 and PCWG3. At the time of submission of this abstract, no dose limiting toxicities have been observed to date in the first 3 cohorts. In the United States, 4 sites are active with additional sites in planning. Additional sites in the US and Australia are currently in start-up. Clinical trial information: NCT04868604 .