Citations

AbstractObjectivesT-cell prolymphocytic leukemia (T-PLL) is a rare mature T-cell leukemia usually characterized by inv(14)(q11.2q32)/t(14;14)(q11.2;q32). In this study, we aimed to investigate the clinicopathologic features and molecular profile of T-PLL associated with t(X;14)(q28;q11.2).MethodsThe study group included 10 women and 5 men with a median age of 64 years. All 15 patients had a diagnosis of T-PLL with t(X;14)(q28;q11.2).ResultsAll 15 patients had lymphocytosis at initial diagnosis. Morphologically, the leukemic cells had features of prolymphocytes in 11 patients, small cell variant in 3, and cerebriform variant in 1. All 15 patients had hypercellular bone marrow with an interstitial infiltrate in 12 (80%) cases. By flow cytometry, the leukemic cells were surface CD3+/CD5+/CD7+/CD26+/CD52+/TCR α/β+ in 15 (100%) cases, CD2+ in 14 (93%) cases, CD4+/CD8+ in 8 (53%) cases, CD4+/CD8– in 6 (40%) cases, and CD4–/CD8 + in 1 (7%) case. At the cytogenetic level, complex karyotypes with t(X;14)(q28;q11.2) were seen in all 15 patients assessed. Mutational analysis showed mutations of JAK3 in 5 of 6 and STAT5B p.N642H in 2 of 6 patients. Patients received variable treatments, including 12 with alemtuzumab. After a median follow-up of 17.2 months, 8 of 15 (53%) patients died.ConclusionsT-PLL with t(X;14)(q28;q11.2) frequently shows a complex karyotype and mutations involving JAK/STAT pathway, and it is an aggressive disease with a poor outcome.

Abstract Background: Two poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) are currently FDA-approved for the treatment of HER2-negative metastatic breast cancer (MBC) in carriers of germline pathogenic variants (PVs) in BRCA1 or BRCA2 (BRCA1/2). This study explores the clinical outcomes of MBC patients treated with a PARPi. Methods: In this retrospective study, we included MBC patients treated with a PARPi between January 2017 and February 2022 at Mayo Clinic (Minnesota, Arizona, Florida, and Mayo Clinic Health Systems). We used the Kaplan Meier method to estimate the time-to-treatment-failure (TTF) and the log-rank test to compare different subsets. In addition, predictors of TTF were identified in a multivariate cox-proportional hazard regression model, including age at PARPi initiation, race, ethnicity, histology, estrogen receptor (ER), progesterone receptor (PR), and HER2 expression of the tumor, the number of prior therapies, type of PARPi, and PV carrier status (germline BRCA1/2 or PALB2 vs. somatic BRCA1/2 vs. other). Results: Sixty-five patients treated with PARPi (olaparib: 51; talazoparib: 14) were included in the final analysis. Fifty-five patients were carriers of germline PVs in BRCA1 (n=24, 37%), BRCA2 (n=27, 42%) or PALB2 (n=4, 6%), whereas ten patients (15%) had no germline PVs but the tumor had a somatic mutation in the homologous recombination-related (HRR) genes (7 in BRCA1/2, 2 in ATM, and 1 in CDKN2A and CDH1). At the data cutoff, 48 (74%) patients had discontinued PARPi due to progression or death. Fifteen (23%) patients required a dose reduction due to side effects. Occurrence of grade ≥ 3 side effects: anemia in 8, fatigue in 4, neutropenia in 2, and thrombocytopenia in 2 patients. Eight (15.7%) patients in the olaparib group and seven (50%) patients in the talazoparib group required a dose reduction for side effects. No patient on olaparib required drug discontinuation due to side effects, whereas two patients on talazoparib were switched to olaparib due to cytopenias and could tolerate olaparib. Median TTF in the overall population was 8 months (95% confidence interval [CI]: 6.4 – 9.6), and there was no difference (p=0.64) in TTF between the olaparib and talazoparib groups. Median TTF in the germline BRCA1, BRCA2, and PALB2 PV carriers were 7, 8, and 11 months, respectively (p=0.57). Among patients with somatic BRCA1/2 mutations, the median TTF was 4 months. Numerically, patients with HER2-positive tumors (n=8) had a shorter TTF compared to HER2-negative tumors (Median TTF: 4 vs. 8 months, p=0.098). No significant difference in TTF was observed by ER or PR status of the tumor, age at initiation of PARPi, the number of prior therapies, and prior use of platinum-based chemotherapy or CDK4/6 inhibitors. In multivariate analysis, HER2 positivity (hazard ratio [HR]: 8.0, 95% CI: 2.2 – 29.4, p=0.002), somatic BRCA1/2 mutations (HR: 7.6, 95% CI: 1.2 – 50.0, p=0.03) and somatic mutations in other HRR genes (HR: 19.1, 95% CI: 3.1 – 118.6, p=0.002) were associated with worse TTF. Conclusions: In the real world, PARPi were well-tolerated with promising time-to-treatment-failure (TTF) benefits comparable to data from clinical trials. Notably, relatively shorter TTF was observed in patients with somatic BRCA1/2 and other HRR gene mutations and HER2-positive MBC. These findings improve our understanding of the role of PARPi in MBC and will help to guide treatment decisions with PARPi in the clinical setting. Citation Format: Nusrat Jahan, Jodi Taraba, Karthik V. Giridhar, Roberto A. Leon-Ferre, Amye J. Tevaarwerk, Elizabeth Cathcart-Rake, Ciara C. O’Sullivan, Prema Peethambaram, Timothy J. Hobday, Kathryn Ruddy, Lida A. Mina, Pooja Advani, Felipe Batalini, Matthew P. Goetz, Tufia C. Haddad, Fergus J. Couch, Siddhartha Yadav. Clinical outcomes of metastatic breast cancer patients treated with poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi): the Mayo Clinic experience [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-22.

As cellular therapies gradually become the mainstay of treatment for several nonmalignant diseases, there appears to be varied accessibility to these therapies globally. Despite considerable burden of nonmalignant conditions, such as sickle cell disease, thalassemia, and aplastic anemia in populations of low–middle-income countries, the utilization of cellular therapies remain sparse because of lack of resources. Globally, the frequency of hematopoietic stem cell transplant (HSCT) has increased disproportionately in countries with higher gross national income (GNI) per capita, governmental healthcare expenditures, and a high human development index. This leads to a large subset of international patients seeking care in the United States. This review summarizes the unique set of challenges that often arise when offering sophisticated therapies such as HSCT to international patients constituting of cross-cultural, logistical, financial, and medical challenges and the opportunities that are available to bridge the gap.

AbstractAlthough adults aged 65 years or older make up a strong majority of cancer patients, their underrepresentation in cancer clinical trials leads to the lack of representative data to guide evidence-based therapeutic decisions in this patient population. The Trial Design Working Group, convened as part of the workshop titled, Engaging Older Adults in the National Cancer Institute Clinical Trials Network: Challenges and Opportunities, recommended study designs and design elements that could improve accrual of older adults in National Cancer Institute–funded clinical trials. These include trials that are specifically designed to enroll older adults, trials that include a cohort of older patients (parallel cohort, stratified cohort, or embedded cohort), and trials with pragmatic design elements to facilitate enrollment of older adults. This manuscript provides brief descriptions of the recommended designs, examples of successful trials, and considerations for implementation of these designs.As with any clinical trial, the scientific questions and trial objectives should drive the study design, the selection of endpoints and intervention, and eligibility criteria. When designing trials that include older adults, the heterogeneity of fitness levels is an important consideration as fitness can influence accrual rates and outcomes. Appropriately incorporating geriatric assessments can help identify the optimal subset of older patients for inclusion and minimize selection bias. Incorporating pragmatic design elements to reduce the burden on trial participants as well as on accruing sites and retaining essential elements to ensure that the main goal of the trial can be accomplished can enhance enrollment without compromising the integrity of trials.

Antimicrobial resistance (AMR) is a well-known global threat due to the subsequent increase in antimicrobial usage. Several antimicrobial stewardship (AMS) strategies have been implemented to curb irrational prescribing and reduce the AMR burden. However, since the beginning of the COVID-19 pandemic, it has enormously impacted the healthcare system and jeopardized public health, causing millions of deaths globally. Our semi-structured qualitative study aimed to explore the impact of COVID-19 on AMS activities in the UK hospitals. Seventeen interviews were conducted with health care professionals who were part of AMS teams (consultant medical microbiologists, infectious disease consultants, antimicrobial pharmacists). Interviews were audio-recorded and transcribed. An inductive thematic framework was adopted to analyse and create the themes. After agreement of the hierarchical framework definition, all transcripts were coded accordingly. Four main themes and 15 sub-themes were identified. These main themes were: (1) AMS activities or strategies before and during the pandemic; (2) challenges to implementing AMS activities before and during the pandemic; (3) information from public authorities on AMS during the pandemic; and (4) new AMS activities/strategies adopted during the pandemic. Staff vacancies, redeploying of AMS staff to other duties and meeting the burden related to the COVID-19 and lack of resources were the most frequently identified contributing factors to withheld AMS activities during the pandemic. However, modifications to the hybrid working environment, i.e., remote or flexible working, allowed for resumption of AMS activities including virtual ward rounds, virtual meetings and other activities. Further research needs to assess the impact of the hybrid delivery system on AMS activities.

ImportanceCytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.ObjectiveTo determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.ExposuresImmunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).Main Outcomes and MeasuresThe primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.ResultsThe median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).Conclusions and RelevanceThis cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.Trial RegistrationClinicalTrials.gov Identifier: NCT04354701

Abstract Purpose: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse model. Defactinib is a highly potent oral FAK inhibitor that has a tolerable safety profile. Patients and Methods: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a recommended phase II dose (RP2D). In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had stable disease (SD) after at least 4 months of standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and posttreatment tumor biopsies were performed to evaluate tumor immunity. Results: The triple drug combination was well-tolerated, with no dose-limiting toxicities. Among 20 treated patients with refractory PDAC, the disease control rate (DCR) was 80%, with one partial response (PR) and 15 SDs, and the median progression-free survival (PFS) and overall survival (OS) were 3.6 and 7.8 months, respectively. Among 10 evaluable patients in the maintenance cohort, DCR was 70% with one PR and six SDs. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS on study treatment were 5.0 and 8.3 months, respectively. Conclusions: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated and safe, had promising preliminary efficacy, and showed biomarker activity in infiltrative T lymphocytes. Efficacy of this strategy may require incorporation of more potent chemotherapy in future studies.