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Cancer Reports (Hoboken, N.J.) Feb 2024Mercaptopurine is an important component of acute lymphoblastic leukemia (ALL) and lymphoma (LLy) maintenance therapy. The 6-thioguanine nucleosides (6-TGN) are believed...
Assessment on the use of allopurinol to improve safety and efficacy of mercaptopurine in pediatric patients with Acute Lymphoblastic Leukemia and Lymphoma during maintenance therapy.
BACKGROUND
Mercaptopurine is an important component of acute lymphoblastic leukemia (ALL) and lymphoma (LLy) maintenance therapy. The 6-thioguanine nucleosides (6-TGN) are believed to be the primary contributor to myelosuppression and immunosuppressive effects, while 6-methylmercaptopurine (6-MMPN) is believed to be responsible for several toxicities including hepatotoxicity, pancreatitis, and hypoglycemia. Previous reports suggest the addition of allopurinol may reduce these toxicities.
AIMS
To assess the use of allopurinol to improve both safety and efficacy of mercaptopurine in pediatric patients with ALL and LLy during maintenance therapy. Secondary objectives included evaluating patient tolerability and skewed metabolism. In addition, we also analyzed mercaptopurine daily dose reduction upon allopurinol initiation.
METHODS AND RESULTS
The primary endpoint was time within goal ANC prior to and after initiation of allopurinol. Secondary endpoints included; improvement in selective toxicities (hepatotoxicity, pancreatitis, and hypoglycemia) and 6-MMPN to 6-TGN ratio prior to and after allopurinol initiation. In addition, an exploratory endpoint assessing mercaptopurine daily dose reduction prior to and after allopurinol initiation was included. Sixteen patients met inclusion criteria and 15 (94%) of which were included in this study. Median percent of maintenance days within goal ANC prior to and after initiation of allopurinol was 27.8 (IQR 22.6-44.9) and 41.6 (IQR 20.2-58.2) respectively. All patients experienced selective toxicities; 15 (100%) hepatotoxicity, 1 (7%) pancreatitis, and 3 (20%) hypoglycemia. Improvement of toxicities was seen in 13/15 (87%), 1/1 (100%), and 2/3 (67%) respectively. Average 6-MMPN:6-TGN ratio prior to allopurinol initiation was 304:1 and after, allopurinol initiation improved to 15:1, resulting in a 95% reduction. Average mercaptopurine dose prior to and after allopurinol initiation decreased by about 56% (63 to 28 mg/m /day).
CONCLUSION
Results suggest that the use of allopurinol in pediatric patients with ALL and LLy receiving mercaptopurine during maintenance therapy is both safe and effective.
Topics: Humans; Child; Mercaptopurine; Allopurinol; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hypoglycemia; Drug-Related Side Effects and Adverse Reactions; Chemical and Drug Induced Liver Injury; Lymphoma; Pancreatitis
PubMed: 38351548
DOI: 10.1002/cnr2.1987 -
Neuro-oncology Advances 2024Recurrent glioblastoma (rGBM) has limited treatment options. This phase 1 protocol was designed to study the safety and preliminary efficacy of TPI 287, a central...
BACKGROUND
Recurrent glioblastoma (rGBM) has limited treatment options. This phase 1 protocol was designed to study the safety and preliminary efficacy of TPI 287, a central nervous system penetrant microtubule stabilizer, in combination with bevacizumab (BEV) for the treatment of rGBM.
METHODS
GBM patients with up to 2 prior relapses without prior exposure to anti-angiogenic therapy were eligible. A standard 3 + 3 design was utilized to determine the maximum tolerated dose (MTD) of TPI 287. Cohorts received TPI 287 at 140-220 mg/m every 3 weeks and BEV 10 mg/kg every 2 weeks during 6-week cycles. An MRI was performed after each cycle, and treatment continued until progression as determined via response assessment in neuro-oncology criteria.
RESULTS
Twenty-four patients were enrolled at 6 centers. Treatment was generally well tolerated. Fatigue, myelosuppression, and peripheral neuropathy were the most common treatment emergent adverse events. Dose-limiting toxicity was not observed, thus the MTD was not determined. Twenty-three patients were evaluable for median and 6-month progression-free survival, which were 5.5 months (mo) and 40%, respectively. Median and 12-month overall survival were 13.4 mo and 64%, respectively. The optimal phase 2 dose was determined to be 200 mg/m.
CONCLUSIONS
TPI 287 can be safely combined with BEV for the treatment of rGBM and preliminary efficacy supports further investigation of this combination.
PubMed: 38327681
DOI: 10.1093/noajnl/vdae009 -
Frontiers in Oncology 2023Human epidermal growth factor 2 () mutations are uncommon in non-small cell lung cancer (NSCLC), and the lack of established, effective, targeted drugs has resulted in a...
Human epidermal growth factor 2 () mutations are uncommon in non-small cell lung cancer (NSCLC), and the lack of established, effective, targeted drugs has resulted in a persistently poor prognosis. Herein, we report the case of a non-smoking, 58-year-old man diagnosed with lung adenocarcinoma (cT3N0M1c, stage IVB) harboring a mutation (Y772_A775dupYVMA) and PD-L1 (-). The patient's Eastern Cooperative Oncology Group performance status (PS) score was assessed as 1. He commenced first-line treatment with chemotherapy, followed by immuno-chemotherapy, and with disease progression, he received HER2-targeted therapy and chemotherapy with an anti-angiogenic agent. However, HER2-targeted therapy, including pan-HER tyrosine kinase inhibitors (afatinib, pyrotinib, and pozitinib) and antibody-drug conjugate (T-DM1), produced only stable disease (SD) as the best response. After the previously described treatment, primary tumor recurrence and multiple brain metastases were observed. Despite the patient's compromised overall physical condition with a PS score of 3-4, he was administered T-DXd in addition to whole-brain radiotherapy (WBRT). Remarkably, both intracranial metastases and primary lesions were significantly reduced, he achieved a partial response (PR), and his PS score increased from 3-4 to 1. He was then treated with T-DXd for almost 9 months until the disease again progressed, and he did not discontinue the drug despite the occurrence of myelosuppression during this period. This is a critical case as it exerted an effective response to T-DXd despite multiple lines therapy, including T-DM1. Simultaneously, despite the occurrence of myelosuppression in the patient during T-DXd, it was controlled after aggressive treatment.
PubMed: 38304028
DOI: 10.3389/fonc.2023.1268260 -
BMC Pharmacology & Toxicology Feb 2024Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment and is highly effective with low-dose intermittent administration. MTX is occasionally used...
Drug-drug interaction assessment based on a large-scale spontaneous reporting system for hepato- and renal-toxicity, and thrombocytopenia with concomitant low-dose methotrexate and analgesics use.
BACKGROUND
Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment and is highly effective with low-dose intermittent administration. MTX is occasionally used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (APAP)/paracetamol for pain or inflammation control. With MTX treatment, the side effects, such as hepatotoxicity, renal failure, and myelosuppression should be considered. These are also seen with analgesics treatment.
METHODS
We used a large spontaneously reported adverse event database (FAERS [JAPIC AERS]) to analyze whether the reporting of adverse events increased upon MTX and analgesic therapy in patients with RA.
RESULTS
After identifying RA cases, the crude reporting odds ratios (cRORs) for hepatotoxicity, renal failure, and thrombocytopenia associated with the use of MTX, APAP, or NSAIDs were calculated by disproportionality analysis, which revealed significantly higher cRORs for these events. No analgesics showed consistent positive signals for drug-drug interaction (DDI) with concomitant low-dose MTX analyzed using four algorithms for DDI interaction (the Ω shrinkage measure, additive or multiplicative, and combination risk ratio models). However, in renal failure and thrombocytopenia, loxoprofen (Ω = 0.08) and piroxicam (Ω = 0.46), and ibuprofen (Ω = 0.74) and ketorolac (Ω = 3.52), respectively, showed positive signals in the Ω shrinkage measure model, and no consistency was found among adverse events or NSAIDs.
CONCLUSIONS
Studies using spontaneous reporting systems have limitations such as reporting bias or lack of patient background; however, the results of our comprehensive analysis support the results of previous clinical or epidemiological studies. This study also demonstrated the usefulness of FAERS for DDI assessment.
Topics: Humans; Methotrexate; Antirheumatic Agents; Acetaminophen; Anti-Inflammatory Agents, Non-Steroidal; Analgesics; Arthritis, Rheumatoid; Thrombocytopenia; Drug Interactions; Chemical and Drug Induced Liver Injury; Renal Insufficiency
PubMed: 38303016
DOI: 10.1186/s40360-024-00738-6 -
Cureus Dec 2023Ovarian cancer, being one of the prevalent gynecological cancers, warrants a therapy that's both effective and well tolerated. After extensive drug testing, combination... (Review)
Review
Comparison of the Efficacy of Cisplatin/Paclitaxel Versus Carboplatin/Paclitaxel in Improving Survival and Quality of Life in the Advanced Ovarian Cancer Patient Population: A Systematic Review and Meta-Analysis of Randomized Control Trials.
Ovarian cancer, being one of the prevalent gynecological cancers, warrants a therapy that's both effective and well tolerated. After extensive drug testing, combination regimens with paclitaxel plus platinum-based agents such as cisplatin/carboplatin and taxanes, have shown promising results for advanced ovarian cancer. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the efficacy of two treatment regimens for advanced ovarian cancer: cisplatin/paclitaxel and carboplatin/paclitaxel. PubMed (Medline), Science Direct, and Cochrane Library were searched from inception to March 2023. The meta-analysis included patients with histologically verified International Federation of Gynaecology and Obstetrics (FIGO) stages IIB to IV ovarian carcinoma who received either carboplatin/paclitaxel or cisplatin/paclitaxel. The primary outcomes were progression-free survival (PFS), overall survival (OS), quality of life (QOL), complete response rate (CRR), and partial response rate (PRR). The revised Cochrane Risk of Bias Tool 2.0 was used to assess the quality of the RCTs The five RCTs chosen for this statistical analysis consisted of a total of 2239 participants, with 1109 receiving paclitaxel/cisplatin for treatment and the remaining 1130 receiving carboplatin/paclitaxel. Among all included outcomes, these reported significant findings: QoL (p-value=0.0002), thrombocytopenia (p=<0.00001), neurological toxicity (p-value=0.003), nausea/vomiting (p-value=<0.00001), myalgia/arthralgia (p-value=0.02), and febrile neutropenia (p-value=0.01). We concluded that the carboplatin/paclitaxel doublet endows a better quality of life (QOL) to patients along with significantly fewer gastrointestinal and neurological toxicities when compared with the cisplatin/paclitaxel combination. However, the myelosuppressive effects of carboplatin/paclitaxel remain a point of concern and may require clinical management.
PubMed: 38264391
DOI: 10.7759/cureus.51011 -
BMC Cancer Jan 2024Paclitaxel liposome (Lipusu) is known to be effective in non-small cell lung cancer (NSCLC) as first-line treatment. This study aimed to evaluate the effectiveness and...
BACKGROUND
Paclitaxel liposome (Lipusu) is known to be effective in non-small cell lung cancer (NSCLC) as first-line treatment. This study aimed to evaluate the effectiveness and safety of paclitaxel liposome based chemotherapy plus PD-1/PD-L1 inhibitor in patients with advanced NSCLC.
METHODS
In this multicenter, retrospective, real-world study, patients with advanced NSCLC who were administered paclitaxel liposome based chemotherapy plus PD-1/PD-L1 inhibitor in three centers (Peking University People's Hospital as the lead center) in China between 2016 and 2022 were included. Progression-free survival (PFS), overall survival (OS), objective response rate, disease control rate, and adverse events (AEs) were evaluated.
RESULTS
A total of 49 patients were included, with 33 (67.3%) receiving paclitaxel liposome based chemotherapy plus PD-1/PD-L1 inhibitor as first-line treatment. There were 34 patients (69.4%) diagnosed with squamous cell carcinoma and 15 (30.6%) with adenocarcinoma. The median follow-up was 20.5 (range: 3.1-41.1) months. The median PFS and OS of all patients were 9.7 months (95% confidence interval [CI], 7.0-12.4) and 30.5 months (95% CI, not evaluable-not evaluable), respectively. Patients with squamous cell carcinoma and adenocarcinoma had median PFS of 11 months (95%CI, 6.5-15.5) and 9.3 months (95%CI, 7.0-12.4), respectively. The median PFS was 9.9 months (95%CI, 7.1-12.7) in patients who received the combined regimen as first-line treatment. Treatment-related AEs of any grade were observed in 25 (51.0%) patients, and AEs of grade 3 or worse were observed in nine patients (18.4%). The most common treatment-related AEs were myelosuppression (14.3%) and fever (10.2%).
CONCLUSIONS
Paclitaxel liposome based chemotherapy plus PD-1/PD-L1 inhibitor prolonged the PFS in advanced NSCLC with acceptable safety, which was worthy of clinical application.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Paclitaxel; Lung Neoplasms; Liposomes; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Retrospective Studies; Immunotherapy; Antineoplastic Combined Chemotherapy Protocols; Adenocarcinoma; Carcinoma, Squamous Cell
PubMed: 38238648
DOI: 10.1186/s12885-024-11860-3 -
Life Science Alliance Mar 2024Non-small cell lung cancer is often diagnosed at advanced stages, and many patients are still treated with classical chemotherapy. The unselective nature of chemotherapy...
Non-small cell lung cancer is often diagnosed at advanced stages, and many patients are still treated with classical chemotherapy. The unselective nature of chemotherapy often results in severe myelosuppression. Previous studies showed that protein-coding mutations could not fully explain the predisposition to myelosuppression. Here, we investigate the possible role of enhancer mutations in myelosuppression susceptibility. We produced transcriptome and promoter-interaction maps (using HiCap) of three blood stem-like cell lines treated with carboplatin or gemcitabine. Taking advantage of publicly available enhancer datasets, we validated HiCap results in silico and in living cells using epigenetic CRISPR technology. We also developed a network approach for interactome analysis and detection of differentially interacting genes. Differential interaction analysis provided additional information on relevant genes and pathways for myelosuppression compared with differential gene expression analysis at the bulk level. Moreover, we showed that enhancers of differentially interacting genes are highly enriched for variants associated with differing levels of myelosuppression. Altogether, our work represents a prominent example of integrative transcriptome and gene regulatory datasets analysis for the functional annotation of noncoding mutations.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Carboplatin; Antineoplastic Agents; Mutation
PubMed: 38228368
DOI: 10.26508/lsa.202302244 -
Lung Cancer (Amsterdam, Netherlands) Feb 2024Trilaciclib is a transient cyclin-dependent kinase 4/6 inhibitor that decreases the incidence of chemotherapy-induced myelosuppression in extensive-stage small cell lung... (Randomized Controlled Trial)
Randomized Controlled Trial
Myeloprotection with trilaciclib in Chinese patients with extensive-stage small cell lung cancer receiving chemotherapy: Results from a randomized, double-blind, placebo-controlled phase III study (TRACES).
INTRODUCTION
Trilaciclib is a transient cyclin-dependent kinase 4/6 inhibitor that decreases the incidence of chemotherapy-induced myelosuppression in extensive-stage small cell lung cancer (ES-SCLC). TRACES study was designed to assess the safety, efficacy and pharmacokinetics (PK) of trilaciclib before chemotherapy in Chinese patients with ES-SCLC.
METHODS
The study included an open-label safety run-in part (Part 1) and double-blinded, placebo-controlled part (Part 2) where patients received trilaciclib or placebo before chemotherapy. Treatment-naïve or previously treated ES-SCLC patients received intravenous trilaciclib (240 mg/m) or placebo before etoposide/carboplatin or topotecan, respectively. Primary endpoints were PK, safety and duration of severe neutropenia (DSN) in Cycle 1 in Part 1 and Part 2. Exploratory endpoints included the effect of trilaciclib on other myeloprotection endpoints, safety and antitumor efficacy.
RESULTS
Overall, 95 Chinese patients were enrolled, of which 12 and 83 patients were in Part 1 and Part 2, respectively. In Part 1, trilaciclib was well tolerated. Non-compartmental analysis results revealed no substantial differences in the main exposure parameters. In Part 2, 41 patients received trilaciclib, and 42 received placebo. Patients in trilaciclib arm vs placebo arm had a clinically and statistically significant decrease in DSN (mean [SD]) in Cycle 1 (0 [1.7] vs 2 [3.0] days; P = 0.0003), with improvements in additional neutrophil, red blood cell, and platelet measures. After a median follow-up of 14.1 months, the median overall survival was 12.0 months in trilaciclib arm and 8.8 months in placebo arm (HR, 0.69; 95 % CI: 0.40-1.22). Median progression-free survival was 4.8 months and 4.3 months, respectively (HR, 0.86; 95 % CI: 0.53-1.39). Trilaciclib had a well-tolerated safety profile.
CONCLUSIONS
Trilaciclib in the Chinese population demonstrated a similar PK and safety profile as seen in other global trials. There was significant reduction of DSN in Cycle 1, thereby substantiating the myeloprotective effects of trilaciclib in Chinese ES-SCLC patients.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Carboplatin; Etoposide; Neutropenia; China; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Pyrimidines; Pyrroles
PubMed: 38224653
DOI: 10.1016/j.lungcan.2023.107455 -
International Journal of Women's Health 2024Tumor-infiltrating lymphocytes (TILs) therapy is one of the most promising adoptive T cell therapies, which has shown great clinical efficacy against several solid...
INTRODUCTION
Tumor-infiltrating lymphocytes (TILs) therapy is one of the most promising adoptive T cell therapies, which has shown great clinical efficacy against several solid malignancies. Nevertheless, clinical response to TILs mono-therapy in Asian patients with recurrent cervical cancer has not been well reported.
CASE PRESENTATION
Here, we report two patients who were diagnosed with metastatic cervical cancer and tumor progression following multiple conventional treatments. In particular, one of the patients has a history of severe myelosuppression after chemotherapy. The patients received lymphodepletion therapy, which consisted of cyclophosphamide (30mg/kg) for 2 days, followed by Fludarabine (25mg/m) for 5 days, approximately 24 hr before receiving intravenous autologous TILs infusion. These two patients then received high doses of IL-2 for 10 days with the purpose of maintaining T cell survival and proliferation. Patient 1 experienced clinical partial response (PR) at 6 weeks post TILs infusion and a 33% tumor shrinkage at 12 weeks follow-up, and patient 2 was evaluated as stable disease (SD) at 6 weeks post treatment. Mild and manageable adverse events were observed and soon subsided after the TILs treatment. A time-course study examining the peripheral blood cell count and cytokine secretion demonstrated the persistence of infused TILs and long-term immune response.
CONCLUSION
These results suggest that TILs mono-therapy can be a promising treatment strategy for Asian patients with late-stage metastatic cervical cancer even with severe myelosuppression. TILs infusion can induce persistence and a long-term systematic immune response that reversed peripheral CD4+T and CD8+T percentages implying that TILs infusion increased cytotic T cell responses, which is consistent with clinical responses in these patients. Trial registration number: NCT05366478.
PubMed: 38222312
DOI: 10.2147/IJWH.S446768 -
Medicine Jan 2024Neutropenia can be caused by a variety of congenital and acquired factors, with Chemotherapy-induced myelosuppression being the most common cause. Neutropenia...
Neutropenia can be caused by a variety of congenital and acquired factors, with Chemotherapy-induced myelosuppression being the most common cause. Neutropenia significantly affects oral health, leading to the manifestation of oral lesions such as ulcers, fungal and viral infections, and mucositis. This study aims to investigate oral lesions in patients with hematological malignancies who developed neutropenia after chemotherapy. This cross-sectional study included 50 patients with hematological malignancies. The participants were divided into 2 groups: the first group consisted of 25 patients with hematological malignancies who developed chemotherapy-induced neutropenia and the second group consisted of 25 patients with hematological malignancies who did not develop chemotherapy-induced neutropenia. Patients were assigned to one of the groups based on the absolute neutrophil count (ANC). Full oral clinical examination was performed to determine the presence of oral lesions. In the Chemotherapy-Induced Neutropenia group, the most common lesion was ulceration, observed in 12 patients (48%). Fungal infections were the second most common, present in 5 patients (20%), followed by viral infections in 4 patients (15%), and mucositis, which occurred in a single patient (4%). A statistically significant association was found between neutropenia and the presence of oral ulcers (P value = .015). In contrast, in the Chemotherapy group, oral changes were less frequent. Fungal infections were the most common, occurring in 4 patients (15%), followed by oral mucositis in 3 patients (12%). Ulceration and viral infections were the least common, each observed in 1 patient (4%). The frequency of various forms of oral ulcers increases with the severity of neutropenia. However, there was no significant increase in other oral lesions in patients with neutropenia.
Topics: Humans; Cross-Sectional Studies; Mucositis; Oral Ulcer; Syria; Neutropenia; Hematologic Neoplasms; Mycoses; Antineoplastic Agents; Virus Diseases
PubMed: 38215147
DOI: 10.1097/MD.0000000000036780