Myelosuppression Toxicity Research Articles

A biomimetic solution, albumin-doxorubicin molecular complex, targeting tumor and tumor-draining lymph nodes.

Chemotherapy-induced immunologic cell death is haunted by the non-specific distribution of chemotherapeutic drugs and insignificant immune activation effects, which render efforts to inhibit the distant metastasis of tumors frustrated. Given the pivotal role that lymph nodes play in tumor metastasis, it is of vital importance whether the drug delivery to tumor-draining lymph nodes (TDLNs) succeeds. In the current study, we developed a doxorubicin-albumin complex (DOX-HSA) solution with the specific ability to simultaneously target the primary tumor and the TDLNs. DOX-HSA could effectively activate and amplify the immunogenic cell death (ICD) effect in both the tumor tissues and the TDLNs, resulting in increased release of damage-associated molecular patterns (DAMPs), which further promoted phagocytosis and maturation of dendritic cells (DCs), stimulated activation of CD8+T cells, and then significantly enhanced the therapeutic effects of doxorubicin on orthotopic 4T1 tumor-bearing model mice. Therefore, the DOX-HSA solution demonstrated a more prominent ability to control cancer cells and curb metastasis, as well as improved security by reducing cardiotoxicity and myelosuppression toxicity of doxorubicin itself. This DOX-HSA strengthened the synergistic anti-tumor effects based on the ICD effect in combination with traditional chemotherapy, thus providing promising prospects for clinical application.

Complications Of Colchicine Initiation in a Patient with Chronic Kidney Disease

We report a case of a 76-year-old female with stage 4 chronic kidney disease (CKD) who experienced multiple adverse events following the initiation of colchicine for a gout flare. Diarrhea led to further complications, including acute renal failure, hypercalcemia, and bradycardia. The patient additionally developed the less common toxicities of myelosuppression and presumed myopathy, resulting in prolonged hospitalization with persistent functional impairment at the time of discharge. This report highlights the importance of exercising caution when prescribing colchicine to patients with severe CKD. It discusses alternate ways to manage acute gout as well as strategies to minimize the risk of adverse events when using colchicine in this population.

Targeting an Old Foe for Cancer: A Molecular Dynamics Perspective to Unravel the Specific Binding Nature of 2-Methoxy Estradiol to Human β-Tubulin Isotypes.

Microtubules, composed of α- and β-tubulin subunits are crucial for cell division with their dynamic tissue-specificity which is dictated by expression of isotypes. These isotypes differ in carboxy-terminal tails (CTTs), rich in negatively charged acidic residues in addition to the differences in the composition of active site residues. 2-Methoxy estradiol (2-ME) is the first antimicrotubule agent that showed less affinity toward hemopoietic-specific β1 isotype consequently preventing myelosuppression toxicity. The present study focuses on the MD-directed conformational analysis of 2-ME and estimation of its binding affinity in the colchicine binding pocket of various β-tubulin isotypes combined with the α-tubulin isotype, α1B. AlphaFold 2.0 was used to predict the 3D structure of phylogenetically divergent human β-tubulin isotypes in dimer form with α1B. The dimeric complexes were subjected to induced-fit docking with 2-ME. The statistical analysis of docking showed differences in the binding characteristics of 2-ME with different isotypes. The replicas of atom-based molecular dynamic simulations of the best conformation of 2-ME provided insights into the molecular-level details of its binding pattern across the isotypes. Furthermore, the MM/GBSA analyses revealed the specific binding energy profile of 2-ME in β-tubulin isotypes. It also highlighed, 2-ME exhibits the lowest binding affinity toward the β1 isotype as supported by experimental study. The present study may offer useful information for designing next-generation antimicrotubule agents that are more specific and less toxic.

Filgrastim Use in the Treatment of Azathioprine-Induced Myelosuppression Toxicity After Prescription Error in the Feline.

Only one report on the successful use of filgrastim (granulocyte colony-stimulating factor) in cats for severe neutropenia following azathioprine toxicity exists. Here, we report on a case in which a cat was prescribed methimazole but the medication was filled incorrectly with azathioprine tablets and the prescription label indicated a methimazole dosing regimen that was administered for three days before recognition of the error. On presentation, the cat's physical examinations were consistent with previous examinations before ingestion of azathioprine. A complete blood cell count revealed neutropenia and leukopenia. The cat later developed hyporexia, dehydration, and vomiting. Treatment included antinausea and appetite stimulant medications, filgrastim, and antibiotics. Filgrastim given as subcutaneous injections over the course of treatment increased neutrophil cell counts after suppression. The cat made a full recovery after responding to the treatment protocol. Based on the perceived response to filgrastim in this single feline case report, its use can be considered for the treatment of azathioprine-induced neutropenia in cats.

Abstract CT195: First-in-human phase 1 study of WEE1 inhibitor APR-1051 in patients with advanced solid tumors harboring cancer-associated gene alterations

Abstract Background: WEE1 tyrosine kinase plays a key role in cell cycle regulation and DNA damage responses, acting as a principal gatekeeper of the G1-S and G2-M cell cycle checkpoints. Thus, inhibition of WEE1 can result in high cyclin-dependent kinase 1 and 2 activities, leading to aberrant cell cycle progression. Increasing premature entry into mitosis and subsequent apoptosis via WEE1 inhibition is one potential approach to killing cancer cells effectively. APR-1051 is an orally bioavailable, highly potent, small molecule inhibitor of WEE1 that has demonstrated in vivo anti-proliferative activity in multiple cancer cell lines and high selectivity for WEE1 versus polo-like kinases 1, 2, and 3. Increased selectivity for WEE1 may reduce the myelosuppressive toxicity (e.g., limiting Grade 3 toxicities) reported with other WEE1 inhibitors. Methods: The primary aim of this multi-center, open-label Phase I study is to characterize the safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD)/maximum administered dose (MAD) and recommended Phase 2 dose (RP2D) of APR-1051 in patients with advanced solid tumors harboring cancer-associated gene alterations. Secondary objectives include evaluating the pharmacokinetic (PK) properties of APR-1051, assessing the effect of food on its PK, and its preliminary efficacy per RECIST version 1.1. The exploratory objective is to assess the pharmacodynamic effects of APR-1051. For dose escalation, an accelerated titration followed by a BOIN design will be utilized to determine the MAD/MTD. Upon completion of the dose escalation, two suitable doses and schedules of single-agent APR-1051 will be determined for further investigation in dose selection optimization. Key inclusion criteria are age at least 18 years with advanced solid tumor and cancer-associated gene alterations (e.g., amplification/overexpression of CCNE1 or CCNE2, deleterious mutations in FBXW7 or PPP2R1A), ECOG PS 0 or 1, and adequate organ function. Key exclusion criteria are cancer therapy within 3 weeks or at least 5 half-lives, prior radiation therapy at the target lesion except if evidence of disease progression, unresolved therapy-related AEs, investigational agent within 5 half-lives or 30 days of study drug, prior WEE1 inhibitor, CNS metastases or unstable involvement, secondary malignancies that are active and/or require therapy, and concomitant moderate/strong inhibitors/inducers of CYP3A4/5, MDR1, or BCRP. Up to 79 patients will be enrolled at 3 to 5 sites in the United States. Citation Format: Timothy A. Yap, Crystal Miller, David Stenehjem, Eric J. Brown, Mike Carleton, Nadeem Q. Mirza. First-in-human phase 1 study of WEE1 inhibitor APR-1051 in patients with advanced solid tumors harboring cancer-associated gene alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT195.

Efficacy and safety analysis of combination therapy based on mitoxantrone hydrochloride liposome injection (Lipo-MIT) in relapsed/refractory NK/T-cell lymphoma.

Currently, there is no standard treatment for relapsed/refractory NK/T-cell lymphoma (NKTCL). Liposomal mitoxantrone (Lipo-MIT) showed good anti-tumor effect in patients with NKTCL, breaking the limitation of natural resistance of NKTCL to anthracyclines. To further improve the efficacy, we tried a combination therapy based on Lipo-MIT in patients with relapsed/refractory NKTCL. 12 patients with relapsed/refractory NKTCL were enrolled in this retrospective study, all of whom had previously received pegaspargase-based treatments. The salvage treatment was a combination regimen based on Lipo-MIT. The efficacy was evaluated after every two cycles. 11 patients had stage IV NKTCL, and all but one patients had an NRI score of ≥3. The median previous lines of treatment was two (range, 1-4), and five patients were refractory to their last line of treatment. The best response rates were as follows: complete response (CR) in five (41.7%) patients, partial response in five (41.7%) patients, stable disease in one (8.3%) patient, and progressive disease in one (8.3%) patient. At a median follow-up of four months (range, 2-14), seven patients died, with a median PFS of five months and a median OS of seven months. The six-month PFS and OS rate was 44.4% and 52.1%, respectively. All patients had suffered from side effects, among which myelosuppression was most reported. Nine patients had grade three or more myelosuppression, and the median recovery time from myelosuppression was 14 days (2-35 days). Five patients had obvious skin hyperpigmentation, and the CR rate was significantly higher compared with those without skin hyperpigmentation (80% vs. 14.3%, p=0.023). Other side effects included liver insufficiency (N=4), coagulation dysfunction (N=4), acute pancreatitis (N=2), and immunotherapy-related adverse effects (irAEs, N=2). Combination therapy based on Lipo-MIT has a high remission rate for relapsed/refractory NKTCL, but the duration of remission needs to be further extended. Lipo-MIT has obvious myelosuppression toxicity, and active supportive therapy should be given when combined with other cytotoxic drugs.

Preclinical Characterization of the Anti-Leukemia Activity of the CD33/CD16/NKG2D Immune Modulating TriNKET ® BMS-986357 (CC-96191)

CD33 is widely expressed by myeloid cells and is a validated drug target in acute myeloid leukemia (AML), as shown by the benefit of some patients from the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO). However, GO is often ineffective and toxic, prompting interest in more potent CD33-directed therapies. Success of T cell-engaging bispecific antibodies in lymphoid malignancies has raised enthusiasm for similar agents targeting CD33, but toxicities from activated T cells cause significant challenges for their use and provide a strong rationale to explore drugs engaging natural killer (NK) cells. Here, we investigated BMS-986357, a TriNKET ® that activates NK cells via CD16 and NKG2D receptors while targeting CD33. This format was chosen because simultaneous engagement of multiple activating NK cell receptors yields greater cytotoxic activity against neoplastic cells than engagement via a single activating receptor. Surface plasmon resonance analyses showed BMS-986357 simultaneously binds CD33, NKG2D, and CD16a, and co-engagement of NKG2D and CD16a increases the avidity. In the presence of primary human NK cells from healthy donors or a human NK cell line, the TriNKET ® demonstrated broad cytolytic anti-leukemia activity in a strictly CD33-dependent manner using a panel of CD33-expressing or CD33-deficient/deleted acute leukemia cells. Consistent with this, removing the CD33 binding domain rendered BMS-986357 ineffective against CD33+ AML cells. Drug-induced cytotoxicity was greater with BMS-986357 than with monoclonal CD33 antibodies, including lintuzumab and an afucosylated antibody with enhanced NK function, demonstrating the benefit of the TriNKET ® format. Compared to BMS-986357, substantially less cytotoxicity was observed with an Fc-mutant variant of BMS-986357 that abrogates binding to CD16a or an NKG2D dead-arm TriNKET ®, and cytolytic effects were reduced with a CD16-deficient NK cell line vs. a CD16-expressing subline, indicating maximal efficacy of BMS-986357 required co-engagement of CD16a and NKG2D. Using sublines of OCI-AML3 and KG-1 cells (both cell lines with low endogenous CD33 expression) to overexpress wild-type CD33 at increasing levels, we found low abundance of CD33 curtailed BMS-986357-induced cytotoxicity. Flow cytometric binding studies identified BMS-986357 to recognize the membrane-distal V-set domain of CD33. Unlike GO, BMS-986357-mediated cytolysis was not affected by over-expression of ABC transporter proteins by AML cells. The potency but not maximal activity of BMS-986357 was reduced by super-physiologic concentrations of soluble CD33; in contrast, the soluble form of the NKG2D ligand MICA did not impact TriNKET ® activity. In the presence of CD33+ AML cells, BMS-986357 activated NK cells but not T cells from healthy donor peripheral blood mononuclear cells and produced similar levels of maximum cytolysis as a CD33/CD3 bispecific antibody. Despite this, BMS-986357 elicited 10 to >100-fold lower soluble cytokine levels including IFN-γ, TNF, IL-6, and GM-CSF than a CD33/CD3 bispecific antibody, suggesting BMS-986357 has the potential for CD33/CD3 bispecific-like efficacy without the associated risk of cytokine release syndrome. Finally, in bone marrow specimens from patients with AML, BMS-986357 killed AML cells but not normal monocytes, suggesting selectivity of drug-induced cytotoxicity toward neoplastic cells, consistent with the notion NK cells are capable to differentiate between healthy and leukemic CD33+ cells. This selectivity suggests BMS-986357 may produce less myelosuppressive toxicity than what has been observed with CD33 targeting antibody-drug conjugates. In summary, our findings demonstrate that BMS-986357 TriNKET ® has potent CD33-dependent cytolytic activity in vitro against human AML cells, supporting the drug's exploration in early phase clinical trials. One such trial (NCT04789655) has opened accrual for adults with relapsed/refractory AML.

Outcomes and Hospital Resource Utilization Associated with Decreased Ven Exposure in Acute Myeloid Leukemia Patients: A Real-World Retrospective Review

Patients (pts) with acute myeloid leukemia who are ineligible for intensive chemotherapy are treated with hypomethylating agent (HMA) and Venetoclax (Ven). We previously reported outcomes on a cohort of our pts hospitalized for induction therapy demonstrating that the majority of pts required Ven exposure de-escalation. Despite its widely accepted clinical practice, no prospective study has evaluated the efficacy in retaining remission or the tolerability of less Ven exposure per cycle (cyc). Additionally, there is no study evaluating the effect of delaying treatment secondary to its myelosuppressive toxicities. We aim to present outcome data on a large cohort of all AML pts treated with HMA + Ven within our healthcare system. We queried Northwell Cancer Institute's electronic health records to identify all pts with AML who received at least one cyc of Ven and HMA between January 2019 and December 2022. Groups for analysis were created for pts who received at least 3 cyc of HMA and Ven based on the median Ven exposure days per cyc (≤ 14 days or ≥ 15 days) and the median days between cyc (≤ 34 or ≥ 35 days) excluding cyc 1 and 2. Median relapse-free survival (mRFS) and median event-free survival (mEFS) in months (m) were defined by ELN 2022 criteria. Pts who received allogeneic transplants (n=4) were excluded from survival evaluations. Kaplan-Meier (KM) method and log rank testing was used to compare time to event data. We identified 142 AML pts who received at least 1 cyc of Ven + HMA. Pts had an ORR of 42%, mEFS of 4m and mOS of 9.6m. The median age was 77. Only 76 pts received 3 or more cyc of HMA + Ven with mRFS 11.6m of and mOS of 20.6m. Of these pts, 39 had AML with myelodysplastic changes, 29 had De Novo AML and 8 had secondary AML. 75% of pts received HMA + Ven as first line treatment. Utilizing the 2022 ELN risk categories (Dohner et al, Blood 2022), 12 had favorable risk, 12 had intermediate risk and 52 had adverse risk. 93% had treatment regimen modifications by either reduced Ven/cyc or increased cyc intervals. All prognostic indicators appeared evenly dispersed among the groups. Pts with ≤14 days of Ven/cyc (n=35) had a median of 7 cyc (range 3-24) and remained on treatment for a median of 11.3 m. Meanwhile, pts with ≥15 days/cyc (n=41) had a median of 5 cyc (range 3-24) with a median of 10.1m on treatment. The ≤14 days of Ven/cyc group had significantly improved RFS (15.8m vs 8.7m) and OS (24.7m vs 11.3m) compared to the group of pts receiving ≥15 days/cyc (p <0.01). Additionally, there was a decrease in number of hospital days, RBC and platelet transfusions in this group compared to the ≥15 days/cyc group (figure 2). 66% of pts (n=50) required increased time interval between cycles. Both ≤ 34 and ≥ 35 days cyc interval groups completed median of 6 cyc. No significant difference was found in mRFS (11.6m vs 11.8m) or mOS (15.1m vs 21.8m). However, there was a reduction in hospital days, pRBC and platelet transfusions in the ≥ 35 day interval group (figure 2). The overall response rate, mRFS and mOS of all 144 patients seem to be decreased compared to reported prospective trials. This may be due to differences in frailty in our pt population. Although limited by the bias of retrospective analyses, our evaluation of pts outcomes demonstrates a statistically and clinically significant improvement in mRFS and mOS in pts with decreased Ven days/cycle. The majority of pts had Ven/cycle decreased by cycle 3 and most were intermediate or high risk. Our results also highlight the decrease in hospital resource utilization and transfusion needs in this group which may lead to improved quality of life and decreased costs. The ≤14days Ven/cycle group had improved survival compared to the VIALE-A and DEC10-VEN trial despite a larger proportion of our pts having adverse risk. We hypothesize that this improvement is likely multifactorial secondary to decreased mortality from higher Ven exposure, improved tolerance causing increased HMA exposure from timely dosage and from a theoretically possible decreased intracellular adaptive mechanisms generating resistance from continuous Bcl-2 inhibition. This emphasizes the need for continued reporting of outcomes of therapy with HMA/Ven. Additionally, due to the clinically significant improvement in mRFS and mOS, a prospective trial evaluating the efficacy, tolerability, and impact on quality of life of reduced Ven exposure/cyc should be considered.

Efficacy and Safety Analysis of Combination Therapy Based on Liposomal Mitoxantrone (Lipo-MIT) in Relapsed/Refractory NK/T-Cell Lymphoma

Background: Currently, there is no standard treatment for relapsed/refractory NK/T-cell lymphoma (NKTCL), which is characterized by highly aggressive and poor prognosis. New drugs are urgently needed to improve the therapeutic effect. Liposomal mitoxantrone (Lipo-MIT) is approved in China for the treatment of relapsed or refractory peripheral T-cell lymphoma patients who have received at least one line standard therapy previously. Phase II study data showed that the objective response rate (ORR) of patients after monotherapy was 41.7% and the complete response rate (CR) was 23.1%. Progression-free survival (PFS) was 8.5 months. Lipo-MIT showed excellent anti-tumor effect in patients with NKTCL subtype, with an ORR of 42.9%, which broke the limitation of natural resistance of NKTCL to anthracyclines. To further improve the efficacy, we tried a combination therapy based on Lipo-MIT in patients with relapsed/refractory NKTCL. Herein we will report its efficacy and safety. Methods: Nine patients with relapsed/refractory NKTCL were enrolled in this study, all of whom had previously received pegaspargase-based combination chemotherapy. The salvage treatment was a combination regimen based on Lipo-MIT. The efficacy was evaluated after every 2 cycles using PET-CT or MRI scan, and hematological and non-hematological adverse events were collected after treatment. Progression-free survival (PFS) was defined as the time from initiation of Lipo-MIT to disease progression, recurrence, death, or last follow-up. Overall survival time (OS) was defined as the time from initiation of Lipo-MIT to death from all causes or the last follow-up. Results: The median age of the nine patients was 53 years old (17-67 years old), and the male-female ratio was 7:2. Eight patients had stage IV NKTCL, one was stage II NKTCL, and all patients had an NRI score of ≥3. The median number of previous treatment lines was 2 (1-4). Three patients had recurrent NKTCL, and six patients had refractory disease to previous treatments, among whom two patients had concurrent hemophagocytic syndrome. The salvage treatment regimens were as follows: Lipo-MIT + pegaspargase + dexamethasone (N=3); Lipo-MIT + pegaspargase + dexamethasone +PD1 monoclonal antibody (N=2); Lipo-MIT +PD1 monoclonal antibody + dexamethasone (N=2); Lipo-MIT + etoposide + pegaspargase + dexamethasone (N=2). Efficacy was evaluable in all patients and the median number of treatment cycles was 3 (2-6). The best response rates were as follows: complete response in 3 (33.3%) patients, partial response in 4 (44.4%) patients, stable disease in 1 (11.1%) patient, and progressive disease in 1 (11.1%) patient. At a median follow-up of 4 months (2-13 months), 6 patients died, including 5 from disease progression and 1 from pegaspargase -associated acute pancreatitis, with a median PFS of 5 months and a median OS of 7 months. One patient underwent allogeneic hematopoietic stem cell transplantation after achieving a complete response and has been disease-free for more than 13 months now. The main adverse reactions of Lipo-MIT combination regimen were grade 3 or more bone marrow suppression (N=7), skin cyanosis (N=4), liver insufficiency (N=4), coagulation dysfunction (N=4), acute pancreatitis (N=1). The median recovery time from myelosuppression was 17 days (6-35 days). There was no correlation between skin cyanosis and efficacy. Conclusion: Combination therapy based on Lipo-MIT has a high remission rate for relapsed/refractory NKTCL, but the duration of remission needs to be further extended, and subsequent allogeneic hematopoietic stem cell transplantation may prolong survival. Lipo-MIT has obvious myelosuppression toxicity, and active supportive therapy should be given when combined with other cytotoxic drugs. In the future, it is worthwhile to conduct prospective clinical trials to explore the optimal combination therapy based on Lipo-MIT in relapsed/refractory NKTCL.

Tenosynovial giant cell tumor: a case report

BackgroundThis case reports the synchronous diagnosis of two rare unrelated diseases; leiomyosarcoma and tenosynovial giant cell tumor of the knee. It focuses on the challenges of diagnosing tenosynovial giant cell tumor, including cognitive biases in clinical medicine that delay diagnosis. It also demonstrates the pathogenic etiology of tenosynovial giant cell tumor, evidenced by the transient deterioration of the patients’ knee symptoms following the administration of prophylactic granulocyte colony-stimulating factor given as part of the chemotherapeutic regime for leiomyosarcoma.Case presentationA 37-year-old Caucasian man presented with a left groin lump and left knee pain with swelling and locking. Investigations including positron emission tomography-computed tomography and biopsy revealed leiomyosarcoma in a lymph node likely related to the spermatic cord, with high-grade uptake in the left knee that was presumed to be the primary site. His knee symptoms temporarily worsened each time granulocyte colony-stimulating factor was administered with each cycle of chemotherapy for leiomyosarcoma to help combat myelosuppressive toxicity. Subsequent magnetic resonance imaging and biopsy of the knee confirmed a tenosynovial giant cell tumor. His knee symptoms relating to the tenosynovial giant cell tumor improved following the completion of his leiomyosarcoma treatment.ConclusionsTenosynovial giant cell tumor remains a diagnostic challenge. We discuss the key clinical features and investigations that aid prompt diagnosis. The National Comprehensive Cancer Network clinical practice guidelines for soft tissue sarcoma have recently been updated to include the pharmacological management of tenosynovial giant cell tumor. Our case discussion provides an up-to-date review of the evidence for optimal management of patients with tenosynovial giant cell tumor, with a particular focus on novel pharmacological options that exploit underlying pathogenesis.

Elective Nodal Irradiation vs. Involved-Field Irradiation for Stage Ⅱ-Ⅳ Cervical Esophageal Squamous Cell Carcinoma Patients Undergoing Definitive Concurrent Chemoradiotherapy: A Retrospective Propensity Study with Eight-Year Survival Outcomes

Definitive concurrent chemoradiotherapy (dCCRT) is suggested as the standard treatment for cervical esophageal squamous cell carcinoma (CESCC). This retrospective propensity study compared the eight-year survival outcomes and acute treatment toxicities of these patients treated with elective nodal irradiation (ENI) versus involved-field irradiation (IFI). Patients with stage Ⅱ-Ⅳ CESCC treated with dCCRT in our institution between January 1, 2007 and December 31, 2020 were enrolled in the study. All the patients were restaged according to the American Joint Commission (AJCC) 8th edition criteria. The propensity score matching (PSM) was used to minimize the effects of treatment selection bias and potential confounding factors including sex, age, ECOG score, clinical T stage (cT), clinical N stage (cN), clinical TNM stage (cTNM) and radiation dose between the ENI group and IFI group. Survival and the prognostic factors were evaluated. The 131 eligible patients underwent ENI (60 patients, 45.8%) or IFI (71 patients, 54.2%). The median follow-up time was 95.3 months (range, 28.0-186.2 months) for all the patients. The median OS, 1-, 3-, 5-, and 8-year OS rates were 44.4 months, 87.8%, 55.5%, 39.0%, and 28.3%, respectively. After PSM, there were 49 patients in each group. The median OS, 1-, 3-, 5-, and 8-year OS rates for ENI and IFI group were 32.0 months, 83.7%, 48.9%, 38.8% and 32.4% versus 45.2 months, 89.8%, 52.7%, 38.2%, 26.6%, respectively (P = 0.984; HR 0.99, 95% CI 0.61-1.62). Similar locoregional control was obtained in both groups. The tendency of leukocytopenia and neutropenia was higher in ENI than in IFI (59.2% versus 38.8%; P = 0.068 and 30.6% versus 14.3%; P = 0.089) at the end of dCCRT. Cervical esophageal squamous cell carcinoma patients undergoing definitive concurrent chemoradiotherapy has a satisfactory prognosis with organ conservation. The involved-field irradiation might be a better alternative owing to similar overall survival outcomes and local control with less toxicity of myelosuppression.

Real world experience with conversion from valganciclovir to letermovir for cytomegalovirus prophylaxis: Letermovir reverses leukopenia and avoids mycophenolate dose reduction.

Valganciclovir (VGC) is the gold-standard for cytomegalovirus (CMV) prophylaxis (PPX) after solid organ transplant (SOT). Letermovir (LTV) was recently approved in high-risk kidney transplant and has reduced myelosuppressive toxicity. Conversion from VGC to LTV may be pursued in the setting of leukopenia. It is unknown if this strategy is effective. Adult patients receiving abdominal SOT were included if converted from VGC to LTV between January 1, 2018 and January 31, 2023. Primary objective was to describe the impact of LTV conversion as measured by WBC recovery, mycophenolate modification, and use of GCSF, and prophylaxis efficacy assessed by course completion and breakthrough DNAemia. Secondary objective was to evaluate rates of post-prophylaxis CMV. Seventy five SOT recipients met inclusion criteria. Mean change in WBC in response to LTV conversion by day 14 was +2.02±2.52k/uL. 75%(56/75) of the population did not require mycophenolate adjustment or had their dose increased after conversion. GCSF was required in 38.7%(29/75) prior to conversion; only 21.3%(16/75) of patients required GCSF after conversion. Early termination was uncommon, 14.7%(11/75) stopped due to lack of ongoing insurance approval, only one patient stopped due to adverse effects (1.3%). One patient had clinically significant breakthrough (1.3%) that was successfully managed with VGC. Incidence of post prophylaxis CMV was 40%. Withholding of VGC with LTV conversion may improve leukopenia without need for additional supportive measures. Most importantly, this strategy avoided additional mycophenolate modifications. In our study, LTV was associated with low rates of breakthrough. Post-prophylaxis CMV was similar to VGC prophylaxis.

Elective nodal irradiation versus involved-field irradiation for stage II–IV cervical esophageal squamous cell carcinoma patients undergoing definitive concurrent chemoradiotherapy: a retrospective propensity study with 8-year survival outcomes

BackgroundDefinitive concurrent chemoradiotherapy (dCCRT) is suggested as the standard treatment for cervical esophageal squamous cell carcinoma (CESCC). This retrospective propensity study compared the 8-year survival outcomes and acute treatment toxicities of these patients treated with elective nodal irradiation (ENI) versus involved-field irradiation (IFI).Materials and methodsPatients with stage II–IV CESCC treated with dCCRT at the Fourth Hospital of Hebei Medical University between January 1, 2007 and December 31, 2020 were enrolled in the study. All the patients were restaged according to the American Joint Commission 8th edition criteria. The propensity score matching (PSM) was used to minimize the effects of treatment selection bias and potential confounding factors including sex, age, ECOG score, clinical T stage, clinical N stage, clinical TNM stage and radiation dose between the ENI group and IFI group. Survival and the prognostic factors were evaluated.ResultsThe 131 eligible patients underwent ENI (60 patients, 45.8%) or IFI (71 patients, 54.2%). The median follow-up time was 91.1 months (range, 23.8–182.0 months) for all the patients. The median OS, 1-, 3-, 5-, and 8-year OS rates were 44.4 months, 87.8%, 55.1%, 38.3%, and 27.2%, respectively. After PSM, there were 49 patients in each group. The median OS, 1-, 3-, 5-, and 8-year OS rates for ENI and IFI group were 32.0 months, 83.7%, 48.5%, 38.5% and 31.1% versus 45.2 months, 89.8%, 52.5%, 37.5%, 26.1%, respectively (P = 0.966; HR 0.99, 95% CI 0.61–1.61). Similar locoregional control was obtained in both groups. The tendency of leukocytopenia and neutropenia was higher in ENI than in IFI (59.2% vs. 38.8%; P = 0.068 and 30.6% vs. 14.3%; P = 0.089) at the end of dCCRT.ConclusionCervical esophageal squamous cell carcinoma patients undergoing definitive concurrent chemoradiotherapy has a satisfactory prognosis with organ conservation. The involved-field irradiation might be a better alternative owing to similar overall survival outcomes and local control with less toxicity of myelosuppression.

CBX-12-101: A first-in-human study of CBX-12, an alphalex peptide drug conjugate (PDC) in patients (pts) with advanced or metastatic solid tumors.

3087 Background: Tumor-targeted drug delivery technologies are urgently needed to overcome conventional chemotherapy’s lack of tumor selectivity. Alphalex conjugates, which contain a pH-low insertion peptide (pHLIP), a linker and a payload, are designed to overcome this lack of selectivity. Unlike antibody drug conjugates, alphalex PDCs target tumors in an antigen-agnostic manner. At pH ≥7.0, the peptide is unstructured. In the low-pH tumor microenvironment the peptide forms an alpha helix and inserts directionally into the tumor cell membrane delivering the linker and payload intracellularly where the linker is cleaved releasing the payload in the cytosol. CBX-12 consists of the pH-sensitive peptide, a self-immolating linker, and the topoisomerase 1 (TOP1) inhibitor exatecan. Methods: In this Phase 1 trial, cohorts of pts were treated with escalating doses of CBX-12 in a 3 + 3 design on three dosing schedules: daily x 5 every 3 weeks, daily x 3 every 3 weeks or once weekly. The primary objectives are safety, tolerability and to determine the MTD and/or RP2D. Secondary and exploratory objectives include evaluation of plasma PK of CBX-12 and exatecan, anti-tumor activity per RECIST v1.1, and measurement of anti-drug antibodies. Results: As of 26 Jan 2023, 42 pts have been treated on three schedules. The most frequent treatment-related AEs (TRAEs) were anaemia (42.9%), nausea (38.1%), fatigue (33.3%), ANC and WBC decreased (33.3% each), vomiting (26.2%), diarrhoea (23.8%) and thrombocytopenia (19.0%). The most frequent Gr3/4 TRAEs were ANC decreased (28.6%), anemia (23.8%), WBC decrease (16.7%), thrombocytopenia (14.3%). Dose limiting toxicity was observed in 6 pts: myelosuppression (6 pts) febrile neutropenia (2 pts), and sepsis (2 pts). Responses were observed in 2 of 9 pts with ovarian cancer and 2 of 8 with breast cancer. The MTD on the daily x 3 schedule is 45mg/m2. Dose evaluation continues on the weekly schedule. Conclusions: In this FIH study of a pH-targeting alphalex PDC, CBX-12 demonstrated single-agent antitumor activity including 4 responses with the dominant toxicity of myelosuppression. Phase 2 expansion cohorts are planned in pts with platinum-resistant ovarian cancer and hormone-receptor positive, HER2 negative breast cancer. Clinical trial information: NCT04902872 .

Self-Assembly of a Linear-Dendritic Polymer Containing Cisplatin and Norcantharidin into Raspberry-like Multimicelle Clusters for the Efficient Chemotherapy of Liver Cancer.

Combination chemotherapy has been proved to be an effective strategy in the clinic, and nanoformulations have drawn much attention in the field of drug delivery. However, conventional nanocarriers suffer from shortcomings such as inefficient coloading and undesired molar ratios of the combined drugs, preleakage of cargos during systemic circulation, and lack of cancer-selective drug release. To achieve tumor-specific codelivery of cisplatin (CDDP) and norcantharidin (NCTD) for synergistic treatment of liver cancer, a novel linear-dendritic polymer, termed as G1(PPDC)x, was designed and synthesized, where a prodrug consisting of cisplatin (CDDP) and norcantharidin (NCTD) was conjugated to PEG2000 via ester bonds to fabricate linear polymer-drug conjugates, and the conjugates were subsequently grafted to the terminal hydroxyls of a dendritic polycarbonate core. Benefiting from the hydrogen bond interactions, G1(PPDC)x could spontaneously self-assemble into a unique type of raspberry-like multimicelle clusters in solution (G1(PPDC)x-PMs). G1(PPDC)x-PMs possessed an optimal synergistic ratio of CDDP and NCTD, without obvious premature release or disassembly in biological environments. Intriguingly, upon extravasation into the interstitial tumor tissues, G1(PPDC)x-PMs (132 nm in diameter) could disassemble and reassemble into smaller micelles (40 nm in diameter) in response to the mildly acidic tumor microenvironment, which would enhance the deep tumor penetration and cellular accumulation of drugs. In vivo delivery of G1(PPDC)x-PMs led to a significantly prolonged blood circulation half-life, which is beneficial to achieve sufficient tumor accumulation through the enhanced permeability and retention (EPR) effect. G1(PPDC)x-PMs displayed the best antitumor activity in H22 tumor-bearing mice with a tumor inhibition rate of 78.87%. Meanwhile, G1(PPDC)x-PMs alleviated both myelosuppression toxicities of CDDP and vascular irritation of NCTD. Our results demonstrated that G1(PPDC)x-PMs could serve as an effective drug delivery system for codelivery of CDDP and NCTD to treat liver cancer efficiently.

Phase I study of trifluridine/tipiracil in combination with gemcitabine (gem) and nab-paclitaxel (nab-P) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC).

731 Background: The incidence of PDAC is on the rise and it is predicted to be the 2nd leading cause of cancer related mortality in the next decade. Most patients present with advanced disease at diagnoses with limited systemic treatment options. Fluoropyrimidines are active in PDAC. Lonsurf (L) is an orally administered combination of a thymidine-based nucleic acid analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Preclinical data demonstrate Lonsurf may have activity in 5-FU resistant malignancies. This phase I study combines Gem, nab-P, and L. Methods: Gem and nab-P are dosed on days 1 and 15 IV on a 28 day cycle. L (20-30mg/m2) is dosed twice daily on days 2-6 and 16-20 (table 1). Dose escalation is by 3+3 design. Key eligibility include pts with untreated locally advanced or metastatic PDAC, ECOG 0-1, and adequate hepatic and bone marrow function. Results: 14 pts (median age 62 yrs [range 43-74]) have been enrolled. Dose was initiated at DL1. The first 3 pts were treated without DLT. DL2 exceeded the MTD with 1 patient experiencing grade 3 infection (cholangitis). Dose expansion to 7 patients was completed at DL 1 with no further DLTs. The RP2D is Gem 800mg/m2, Nab-P 100mg/m2, and L 25mg/m2. Of the 10 patients with evaluable disease, 2 (20%) had PR and 7 (70%) had SD. Pts were on study a median of 14 months (range 4 -31+). Most common grade 3/4 AEs include fatigue (46%,) neutropenia (38%), anemia (31%) anorexia (15%), nausea (15%), vomiting (15%), abdominal pain (15%), hyperglycemia (15%). No grade 5 events occurred. Conclusions: The RP2D is Gem 800mg/m2, Nab-P 100mg/m2, and L 25mg/m2. This combination was well tolerated with expected toxicities of myelosuppression with prolonged responses seen. Clinical trial information: NCT04046887 . [Table: see text]

Hydroxyurea Decouples Persistent F-Cell Elevation and Induction of γ-Globin

Mechanisms that control the fetal-to-adult hemoglobin switch are attractive therapeutic targets in sickle cell disease. In this study, we investigated developmental γ-globin silencing in the Townes humanized knock-in mouse model, which harbors a construct containing the human γ-, βA-, and βS-globin genes, and examined the utility of this model in evaluation of pharmacologic induction of fetal hemoglobin (HbF). We studied mouse pups on the day of delivery (P0) to 28 days after birth (P28). Regardless of the hemoglobin genotype (SS, AS, or AA), the proportion of F cells in peripheral blood was 100% at P0, declined sharply to 20% at P2, and was virtually undetectable at P14. Developmental γ-globin silencing in Townes mice was complete at P4 in association with significantly increased BCL11A expression in the primary erythropoietic organs of the mouse. Hydroxyurea given at P2 significantly sustained elevated percentages of F cells in mice at P14. However, the percentage of F cells declined at P14 for treatment begun at P4. A lack of augmentation of γ-globin mRNA in erythroid tissues suggests that the apparent increase in HbF in red cells caused by hydroxyurea was not due to sustained or re-activation of γ-globin transcription, but was instead a function of erythropoiesis suppression. Thus, we provide new details of the hemoglobin switch in the Townes murine model that recapitulates postnatal γ- to β-globin switch in humans and identify the myelosuppressive toxicity of hydroxyurea as a superseding factor in interpreting pharmacologic induction of HbF.

Abstract 1835: NUC-3373 targets the DNA-directed pathway more effectively than 5-FU

Abstract Background: Over the past 60 years, numerous strategies have been employed to enhance the generation of the anticancer metabolite FUDR-MP (FdUMP) by 5-FU and to reduce the generation of toxic metabolites. FUDR-MP, the primary anticancer metabolite of 5-FU, exerts its activity via TS inhibition which results in increased dUMP, depletion of dTMP and DNA damage. 5-FU can also generate FdUTP, which is incorporated into DNA, resulting in DNA damage. 5-FU can also be metabolized to FUTP, which results in the RNA mediated dose-limiting toxicities of myelosuppression and GI tract inflammation. NUC-3373 is a phosphoramidate transformation of FUDR designed specifically to inhibit TS. It generates higher intracellular levels of FUDR-MP, lower levels of toxic metabolites and through its favorable PK profile can be administered via a short infusion. NUC-3373 is a more potent inhibitor of TS than 5-FU and we tested the hypothesis that it more effectively targets DNA than 5-FU. Methods: CRC cells (HCT116 & SW480) were exposed to sub-IC50 doses of NUC-3373 or 5-FU for 6 or 24h. Cells were harvested and analyzed as follows: metabolite levels and incorporation of FdUTP into DNA and FUTP into RNA (using FdUr and FUr as surrogates) by LC-MS and LC-MS/MS. Gene expression of dUTPase was knocked down by siRNA and protein assessed by western blot. Cytotoxicity of NUC-3373 and 5-FU was determined by IC50, measured with sulforhodamine B. Results: NUC-3373 generated significantly higher levels of FUDR-MP compared to 5-FU (AUC >45x greater) resulting in a pronounced increase in dUMP levels (AUC >162x compared to 5-FU). NUC-3373 treated cells incorporated FdUTP into DNA, while incorporation by 5-FU treated cells was below the LLOQ (0.1 nM). NUC-3373 was effective in the presence of dUTPase, but its potency increased after dUTPase knockdown demonstrating that FdUTP incorporation contributes to NUC-3373’s cytotoxicity. At equimolar doses, 42x more FUTP was incorporated into RNA in 5-FU treated cells compared to NUC-3373. Conclusion: NUC-3373 generates higher intracellular levels of the anticancer metabolite FUDR-MP and is a more potent inhibitor of TS than 5-FU resulting in markedly greater accumulation of intracellular dUMP. Additionally, in contrast to 5-FU, NUC-3373 treatment results in incorporation of FdUTP into DNA which indicates that NUC-3373 is a more efficient DNA damaging agent. Through bypassing the FUTP-generation pathway, NUC-3373 avoids the RNA damage that is known to be associated with dose-limiting toxicities such as myelosuppression and GI tract inflammation. This is consistent with the very low rates of FUTP-related toxicities observed in patients treated with NUC-3373 (NCT03428958). By exploiting a more DNA-directed approach, NUC-3373 provides a potentially more effective, safer and convenient therapeutic option than 5-FU for patients with cancer. Citation Format: Jennifer Bré, Alison L. Dickson, Oliver J. Read, Ying Zhang, Clarissa M. Czekster, David J. Harrison. NUC-3373 targets the DNA-directed pathway more effectively than 5-FU [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1835.

Post-radiation cisplatin and etoposide as systemic treatment in newly diagnosed adult medulloblastomas: A retrospective, single institution, longitudinal evaluation of clinical outcomes and toxicity.

e14046 Background: Medulloblastomas are malignancies of the posterior fossa with metastatic potential to the central nervous system. While a common pediatric malignancy, they are rare in adults. Extrapolating treatment regimens from pediatrics to adults is fraught as adults can developmentally tolerate higher radiation doses, but have less bone marrow reserve and therefore risk higher myelosuppressive toxicities with adjuvant systemic therapy. A standard systemic regimen for adults has not been delineated, though craniospinal radiation alone is likely insufficient in most cases. In the absence of well-established guidelines, our institution has historically used a combination of cisplatin (60 mg/m2 on Day 1) and etoposide (60-120 mg/m2 on Days 1-3 or 1-5) repeated in three-week cycles for three to a maximum of six cycles, but the literature to support this regimen is scant. Methods: In this retrospective chart evaluation, we reviewed the medical information of patients who were seen for newly diagnosed adult medulloblastoma between 1995 and 2020 at Johns Hopkins Hospitals. Those who met our pre-specified criteria (adjuvant treatment with etoposide/cisplatin within six months of craniospinal irradiation, sufficient data on toxicity before and after radiation, during chemotherapy, and one month after completion of the regimen, as well as sufficient clinical follow-up) were included in the analysis. Hematological toxicities were graded by NCI CTCAE guidelines. Follow-up for progression and survival were calculated from the end of the last chemotherapy administration and plotted on swimmers plots. Results: Ten out of 74 total adult medulloblastoma patients had adequate data about the tolerability of the regimen and clinical follow-up. Median time to follow-up was 46 months (range 4.5-164 months). Eight patients experienced Grade 3 and 4 hematological toxicities. Seven patients completed their planned treatment course, while two patients discontinued treatment prematurely because of hematological toxicities and one due to ototoxicity and fatigue. Three out of the ten patients progressed post-chemotherapy at 1 month, 24.5 months, and 44 months. Both early-progression patients died (7 and 29.5 months respectively), while the remaining eight are alive without evidence of progression. Conclusions: The data suggest a combination regimen of cisplatin and etoposide after craniospinal radiation in newly diagnosed adult medulloblastoma patients has acceptable toxicity and survival outcomes in this small patient cohort and compare favorably to other limited datasets in the literature. Further study is warranted to validate this as a recommended regimen.

Abstract P025: NUC-3373 is a more potent inhibitor of thymidylate synthase than 5-FU and reduces generation of toxic metabolites

Abstract Background NUC-3373 is a novel anti-cancer agent designed to replace 5-FU, one of the most widely used therapies across a broad range of tumors, including colorectal cancer (CRC). 5-FU exerts its main anti-cancer activity via the active metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), which binds and inhibits thymidylate synthase (TS), preventing the conversion of dUMP into dTMP and disrupting DNA synthesis and repair. NUC-3373, a phosphoramidate transformation of FUDR-MP, is designed to bypass 5-FU resistance mechanisms associated with transport, activation and breakdown, and reduce generation of toxic metabolites including FUTP, which is incorporated into RNA causing myelosuppression and gastrointestinal toxicity, and FBAL which causes hand-foot syndrome. Thymidine supplementation rescues cells from NUC-3373 induced cytotoxicity, supporting a DNA targeted mode of action. The aim of this study was to further evaluate the differences between NUC-3373 and 5-FU. Methods CRC cell lines HCT116 and SW480 were exposed to sub-IC50 doses of NUC-3373 or 5-FU (0.1-25 μM) for 6h. At specific time-points, cells were harvested and analyzed as follows: TS inhibition by western blot, metabolite levels by mass spectrometry (LC-MS & LC-MS/MS) and cell cycle by flow cytometry. In rescue experiments, NUC-3373 and 5-FU were supplemented with thymidine (8 μg/mL) for 24h and cell survival assessed at 96h post-treatment. Results In both cell lines, NUC-3373 was a more potent inhibitor of TS than 5-FU with a higher proportion of TS protein bound to FUDR-MP at low concentrations. At 24h, 10 µM 5-FU was required to achieve the same level of TS binding as 0.1 µM NUC-3373 in HTC116 cells and as 0.5 µM NUC-3373 in SW480 cells. TS inhibition by NUC-3373 was almost maximal by 6 hours and was sustained for at least 48 hours. NUC-3373 generated significantly higher levels (50x) of free FUDR-MP compared to 5-FU, resulting in a more pronounced increase in dUMP levels (5x compared to 5-FU). At 48h, NUC-3373 treated cells remained arrested in S phase, while 5-FU treated cells had reverted to a normal cell cycle. FUTP was present in cells exposed to low doses of 5-FU (0.5 μM) but was not detectable in NUC-3373 treated cells. Finally, thymidine supplementation did not alter cell sensitivity to 5-FU but rescued cells treated with NUC-3373. Conclusion NUC-3373 generates higher intracellular levels of FUDR-MP and is a more potent inhibitor of TS than 5-FU, leading to more pronounced effects on cell cycle arrest and perturbation of the nucleotide pool that can result in misincorporation of uracil into DNA. Furthermore, NUC-3373 did not generate FUTP, consistent with the observation that patients treated with NUC-3373 in clinical studies have experienced much lower rates of FUTP-related toxicities. NUC-3373 is a potent TS inhibitor with a favorable safety profile. Citation Format: Jennifer Bré, Alison L. Dickson, Oliver J. Read, Ying Zhang, Peter Mullen, Clarissa M. Czekster, David J. Harrison. NUC-3373 is a more potent inhibitor of thymidylate synthase than 5-FU and reduces generation of toxic metabolites [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P025.