Search

In a previous study, we showed that folate receptor‐α (FRα) translocates to the nucleus where it acts as a transcription factor and upregulates Hes1, Oct4, Sox2, and Klf4 genes responsible for pluripotency. Here, we show that acetylation and phosphorylation of FRα favor its nuclear translocation in the presence of folate and can cause a phenotypic switch from differentiated glial cells to dedifferentiated cells. shRNA‐FRα mediated knockdown of FRα was used to confirm the role of FRα in dedifferentiation. Ocimum sanctum hydrophilic fraction‐1 treatment not only blocks the folate mediated dedifferentiation of glial cells but also promotes redifferentiation of dedifferentiated glial cells, possibly by reducing the nuclear translocation of ~38 kDa FRα and subsequent interaction with chromatin assembly factor‐1. stem cells 2019;37:1441–1454, Possible mechanisms by which Ocimum sanctum hydrophilic fraction‐1 prevents the formation of folate receptor‐α complex are: (a) the caffeoylquinic acid component of O. sanctum hydrophilic fraction‐1 presumably decreases acetylation of folate receptor‐α by decreasing the acetyl transferase or increasing the deacetylases activity, and subsequent nuclear translocation, and (b) since nuclear folate receptor‐α binds to chromatin assembly factor‐1 in folate‐induced dedifferentiated cells and not in differentiated glial cells, the reduction of folate receptor‐α in the nucleus by O. sanctum hydrophilic fraction‐1 may reactivate chromatin assembly factor‐1 and favor differentiation.

Although acute lymphoblastic leukemia (ALL) is most common in pediatric and adolescent and young adult (AYA) patients, 20% of cases are diagnosed in patients ≥ 55 years old. Use of intensive pediatric regimens in AYA populations has demonstrated excellent tolerability and significant improvements in event-free survival (EFS) and overall survival (OS). The backbone of pediatric regimens includes asparaginase and corticosteroids, both of which are associated with more toxicity in older patients and those with body mass index (BMI) ≥ 30 kg/m which leads to poor tolerance of these regimens. We tested the safety and efficacy of a dose-modified The Cancer and Leukemia Group B 10403 regimen using reduced doses of pegylated (PEG)-asparaginase (ASP) and corticosteroids (RD-10403) in 30 patients with Philadelphia-chromosome negative ALL who were ≥50-year-old and younger adults with significant metabolic or hepatic co-morbidities. The complete remission rate on day 28 was 77%, 3-year EFS was 54%, and estimated 3-year OS was 55%. Grade 3+ toxicity was noted in 40% of patients during induction, and induction-related mortality was 3%. Additional prospective evaluation of RD-10403 is merited to determine efficacy and safety of this regimen and to serve as a framework for chemoimmunotherapy combination therapy.

Background: The CALGB 10403 protocol (10403) is an intensive pediatric regimen that has demonstrated a median event-free survival (EFS) of 78.1 months and an estimated 3-year overall survival (OS) of 73% in adolescents and young adults (18-39 yrs) (AYA) with ALL (Stock et al, Blood 2019). The backbone of this regimen includes pegylated asparaginase (PEG-ASP) and steroids, both of which have significant toxicities that increase with age and co-morbidities including obesity. These toxicities have traditionally precluded extending pediatric-inspired regimens to older pts. We have previously demonstrated that adequate asparaginase activity levels and less toxicity were achieved with reduced PEG-ASP dosing (Derman et al, Leukemia & Lymphoma 2020). Therefore, we performed a single-institution retrospective analysis of AYAs and adults up to age 60 yrs with ALL treated using a modified 10403 regimen with reduced dose PEG-ASP and glucocorticoids to evaluate treatment response. Modifications to PEG-ASP/steroid dosing in patients on a reduced-dose (RD) regimen are summarized in Figure 1. We evaluated characteristics and outcomes of these patients (pts). Methods: Retrospective cohort analysis identified pts with ALL who received RD 10403. RD was defined as receiving ≤ 1000IU/m2 of PEG-ASP along with dexamethasone 10mg/m2 on Days 1-7 and Days 15-21 during induction. Dose reduction for PEG-ASP was made for all pts ≥ 50 years old, body mass index (BMI) ≥ 30, diabetes mellitus and/or underlying liver dysfunction (including cirrhosis, non-alcoholic fatty liver disease; liver chemistry cut-off was not used). In patients with severe metabolic syndromes steroids were further reduced to administration on days 1-7 alone. Patients with CD20+ disease received rituximab during Course I, II, and III. Survival curves (EFS and OS) were constructed using the Kaplan-Meier method and compared with the log-rank test. Results: 30 consecutive pts with Ph negative B-cell or T-cell ALL and treated with RD from 8/2014-4/2019 were identified. Pt characteristics are outlined in Table 1. Median age in RD cohort was 46 years old. 53% of RD patients were identified as having high-risk disease (Ph-like ALL, MLL-rearranged, TP53-mutated, and/or early T-cell precursor (ETP) ALL). Median PEG-ASP dose during induction was 1000IU/m2 and 83% of patients achieved therapeutic asparaginase levels at Day 11 of induction (≥0.1IU/mL). 13 patients received 1000IU/m2, 12 patients received 500IU/m2, 4 patients received 250IU/m2, and 1 patient had PEG-ASP held during induction. Median total dexamethasone dose during induction was 140mg/m2; 22 patients received 140mg/m2, 7 received 70mg/m2, and 1 received 113mg/m2. At least one Grade 3+ toxicity was seen in 40% of patients during induction (hepatotoxicity in 8 pts, thrombosis in 4 patients, pancreatitis in 2 patients). Treatment related mortality (TRM) during induction was 3%; overall TRM attributable to 10403 was 10%. The morphologic complete remission (CR) rate was 77% (n=23) at 28 days. Measurable residual disease (MRD) was assessed by multicolor flow cytometry (sensitivity 10-4) and 18 patients (78% of all patients in a CR) achieved MRD-negativity by Day 28. 8 patients underwent allogeneic stem cell transplant (allo-SCT); 4 in first complete remission (3 with MLL-rearrangement and 1 with persistent MRD positivity) and 4 in a second complete remission (CR2) or later. Of the patients that did not go onto transplant, 6 have completed maintenance therapy per 10403 and 5 are still being treated per 10403. Median EFS of the entire cohort of patients was 54.5 months; estimated 3-year OS was 55% and estimated 3-year EFS was 54% (Figure 2A, 2B). For the 16 high-risk patients, the CR rate was 69% at 28 days and estimated 3-year OS was 61% (Figure 3). Conclusions: Our retrospective analysis demonstrates that a modified 10403 regimen with dose reduction of PEG-ASP and dexamethasone in older adults up to 60 years old or younger patients with comorbid conditions is feasible. We found that the RD 10403 regimen mitigates toxicity while still achieving high post-induction CR and MRD negativity rates. Our preliminary analysis demonstrates encouraging 3-year EFS and OS in this high-risk cohort. Prospective evaluation of RD 10403 for older adults can be recommended. Disclosures Gurbuxani: UpToDate: Honoraria. Liu:BMS: Research Funding; Agios: Honoraria, Other: Regional Advisory board meeting; Karyopharm: Research Funding. Thirman:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Syndax: Research Funding; TG Therapeutics: Research Funding; Tolero: Research Funding. Godley:Invitae, Inc.: Membership on an entity's Board of Directors or advisory committees; UptoDate, Inc.: Honoraria. Odenike:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, NS Pharma, Gilead Sciences, Janssen Oncology, Oncotherapy, Agios, CTI/Baxalta, Aprea: Other: Institutional research funding; Astra Zeneca: Research Funding; Incyte: Other: Institutional research funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Impact Biomedicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Larson:Novartis, Takeda, CVS/Caremark, Celgene, Amgen, Epizyme: Consultancy; Astellas, Celgene, Daiichi Sankyo, Novartis, Rafael Pharmaceuticals, Cellectis, Forty Seven: Research Funding. Stock:Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Research Funding; Novartis: Research Funding; Abbvie: Honoraria, Research Funding; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Honoraria; Research to Practice: Honoraria; American Society of Hematology: Honoraria.

10052 Background: Patients (pts) diagnosed with hematologic malignancies during adolescence & young adulthood (AYA) are a uniquely challenging population who are understood to have robust supportive care needs. Here, we describe their symptom burdens and the feasibility of integrating palliative care into an outpatient, multi-disciplinary AYA leukemia clinic at an academic medical center. Methods: Palliative care was introduced into the AYA clinic in 8/2020 to provide symptom-focused care. Pre-existing clinic services included psychologists, pharmacists, and social workers. All established pts receiving routine follow up were referred by the oncology team to the Supportive Care team, which provided same-day palliative care consultation in the same clinic space with a telehealth option and as needed follow-up. To describe baseline symptom burdens, a random cross-sectional sample of pts completed a multi-domain symptom assessment (SA) using validated self-report instruments including physical (Edmonton Symptom Assessment Scale [ESAS]); emotional (Brief Symptom Inventory-18 [BSI-18]); financial (FACIT-COST); cognitive (Childhood Cancer Survivor Study – Neurocognitive Questionnaire); spiritual (FACIT -Spiritual Well-being Scale); and quality of life (QOL) (FACT-General) measures. All pts have a diagnosis of acute or chronic leukemia and were on active treatment or in survivorship. Results: Over 6 months, 30 pts (median age 29 years at assessment, range 18-45 years) received symptom-focused palliative care over 16 combined clinics with 81 total encounters averaging 5 pts (range 1-8) per clinic. 47% were female. No pts declined palliative care. Pts received on average 2.7 follow up visits (range 1-6), with 50% of encounters resulting in adjustments to medical management. Common issues addressed included pain, muscle cramps, neuropathy, anxiety, insomnia, depression, nausea, and non-pharmacological symptom control remedies. Of 46 pts, 31 (67%) completed the SA (median age 30 years at assessment, range 18-43 years); 48% were female; 84% were on treatment. 100% of pts reported fatigue, and 48% reported > = 1 severe symptom (range 0-7) based on the ESAS with “poor feeling of well-being” as the most common (23%). 45% met criteria for BSI-18 emotional distress, and 45% reported some neurocognitive impairment. Emotional distress (p < 0.01), financial toxicity (p = 0.03), low spiritual well-being (p < 0.01), and presence of pain, nausea, or depression (p < 0.05) were all associated with lower QOL. Conclusions: AYA pts with leukemia undergoing treatment and in survivorship experience high symptom burden with poor QOL. It is feasible to both assess symptom burden and provide early palliative care focused on symptom management in an outpatient, multi-disciplinary clinic setting.

Prenatal folic acid (FA) supplementation prevents neural tube defects. Folate receptor alpha (FRα) is critical for embryonic development, including neural crest (NC) development. Previously we showed that FRα translocates to the nucleus in response to FA, where it acts as a transcription factor. In this study, we examined if FA through interaction with FRα regulates stem cell characteristics of cranial neural crest cells (CNCCs)-critical for normal development. We hypothesized that FRα upregulates coding genes and simultaneously downregulates non-coding miRNA which targets coding genes in CNCCs. Quantitative RT-PCR and chromatin immunoprecipitation showed that FRα upregulates Oct4, Sox2, and Klf4 by binding to their cis-regulator elements-5′ enhancer/promoters defined by H3K27Ac and p300 occupancy. FA via FRα downregulates miRNAs, miR-138 and miR-let-7, which target Oct4 and Trim71 (an Oct4 downstream effector), respectively. Co-immunoprecipitation data suggests that FRα interacts with the Drosha-DGCR8 complex to affect pre-miRNA processing. Transfecting anti-miR-138 or anti-miR-let-7 into non-proliferating neural crest cells (NCCs) derived from Splotch (Sp−/−), restored their proliferation potential. In summary, these results suggest a novel pleiotropic role of FRα: (a) direct activation of Oct4, Sox2, and Klf4 genes; and (b) repression of biogenesis of miRNAs that target these genes or their effector molecules.