-
European Journal of Ophthalmology May 2022To report our experience in the management of cataracts presumably due to intravitreal chemotherapy administration in eyes with vitreous disease associated with...
PURPOSE
To report our experience in the management of cataracts presumably due to intravitreal chemotherapy administration in eyes with vitreous disease associated with retinoblastoma.
METHODS
This retrospective study consisted of a cohort of five eyes of five retinoblastoma patients who developed cataracts secondary to intravitreal chemotherapy administration and who then underwent cataract surgery. All patients underwent lensectomy and anterior vitrectomy with/without intraocular lens implantation via clear corneal approach. All cases were administered intraoperative intravitreal melphalan (35-40 mcg) and topotecan (10-20 mcg) at the end of cataract surgery as a preventive measure against retinoblastoma spread. Injections were repeated as needed in monthly follow-ups. Main outcome measures were enucleation rate and disease-free survival time.
RESULTS
The age at surgery ranged between 5 and 10 years. Follow-up time varied from 12 to 16 months. Treatment-free period before surgery ranged between 3 and 20 months. Time from last injection to cataract detection was: 2, 2, 10, 6, and 7 months; and time from last injection to cataract surgery was: 8, 3, 20, 7, and 15 months in cases 1-5, respectively. None of the eyes required enucleation. Tumor control was achieved in all patients at the end of follow-up.
CONCLUSIONS
Injection of melphalan and topotecan into anterior parts of the vitreous may lead to cataract formation. This can be safely managed with lensectomy and anterior vitrectomy and the use of intravitreal administration of melphalan and topotecan at the conclusion of the surgery as a precautionary measure against the potential risk of extraocular spread.
Topics: Antineoplastic Agents, Alkylating; Cataract; Child; Child, Preschool; Humans; Infant; Intravitreal Injections; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topotecan; Vitreous Body
PubMed: 34082595
DOI: 10.1177/11206721211023317 -
Journal of Proteome Research Jun 2021Multiple myeloma is an incurable hematological malignancy that impacts tens of thousands of people every year in the United States. Treatment for eligible patients...
Multiple myeloma is an incurable hematological malignancy that impacts tens of thousands of people every year in the United States. Treatment for eligible patients involves induction, consolidation with stem cell rescue, and maintenance. High-dose therapy with a DNA alkylating agent, melphalan, remains the primary drug for consolidation therapy in conjunction with autologous stem-cell transplantation; as such, melphalan resistance remains a relevant clinical challenge. Here, we describe a proteometabolomic approach to examine mechanisms of acquired melphalan resistance in two cell line models. Drug metabolism, steady-state metabolomics, activity-based protein profiling (ABPP, data available at PRIDE: PXD019725), acute-treatment metabolomics, and western blot analyses have allowed us to further elucidate metabolic processes associated with melphalan resistance. Proteometabolomic data indicate that drug-resistant cells have higher levels of pentose phosphate pathway metabolites. Purine, pyrimidine, and glutathione metabolisms were commonly altered, and cell-line-specific changes in metabolite levels were observed, which could be linked to the differences in steady-state metabolism of naïve cells. Inhibition of selected enzymes in purine synthesis and pentose phosphate pathways was evaluated to determine their potential to improve melphalan's efficacy. The clinical relevance of these proteometabolomic leads was confirmed by comparison of tumor cell transcriptomes from newly diagnosed MM patients and patients with relapsed disease after treatment with high-dose melphalan and autologous stem-cell transplantation. The observation of common and cell-line-specific changes in metabolite levels suggests that omic approaches will be needed to fully examine melphalan resistance in patient specimens and define personalized strategies to optimize the use of high-dose melphalan.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Metabolomics; Multiple Myeloma; Transplantation, Autologous
PubMed: 34014671
DOI: 10.1021/acs.jproteome.1c00022 -
Expert Review of Clinical Pharmacology Apr 2022Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that takes advantage of increased aminopeptidase activity inside tumor cells to rapidly...
INTRODUCTION
Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that takes advantage of increased aminopeptidase activity inside tumor cells to rapidly release alkylating agents therein. Melflufen in combination with dexamethasone has been evaluated in multiple clinical trials in patients with relapsed/refractory multiple myeloma (MM).
AREAS COVERED
This profile covers the unique mechanism of action of melflufen, the preclinical results supporting its activity in cellular models of resistance to chemotherapy, its activity in animal models of MM, and the clinical pharmacokinetics of melflufen. Findings from clinical trials evaluating melflufen, including the pivotal phase II HORIZON study and the phase III OCEAN study, are discussed.
EXPERT OPINION
Although MM treatment has improved, patients with disease refractory to multiple standard-of-care drug classes face a dismal prognosis. Melflufen demonstrated efficacy and tolerability in select populations, with an initial approval in the United States in patients with ≥ four previous lines of therapy and triple-class-refractory MM. Results from the phase III OCEAN study - currently under discussion with regulatory agencies in the United States and Europe - are more complex and have been put into context herein. Lastly, melflufen provides a proof-of-concept for the utility of the peptide-drug conjugate platform in relapsed/refractory MM.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Europe; Melphalan; Multiple Myeloma; Phenylalanine
PubMed: 35723075
DOI: 10.1080/17512433.2022.2075847 -
Blood Advances Jul 2022The reduced-intensity conditioning regimen, fludarabine and melphalan, is frequently used in allogeneic hematopoietic stem cell transplantation (HSCT). Melphalan and the...
The reduced-intensity conditioning regimen, fludarabine and melphalan, is frequently used in allogeneic hematopoietic stem cell transplantation (HSCT). Melphalan and the active metabolite of fludarabine, F-ara-A, are excreted via the kidneys. Existing methods to assess clearance in this setting are based on serum creatinine, which has known limitations for glomerular filtration rate (GFR) estimation in patients with malignancy. Measured GFR (mGFR) may better predict drug dosing to mitigate toxicity and increase the chances of successful engraftment. The primary objective of this study was to assess the association between mGFR and risk for nonrelapse mortality (NRM) in patients who have undergone allogeneic HSCT receiving conditioning with fludarabine and melphalan. In the 109 included patients, mGFR <65 mL/min/1.73 m2 predicted a significantly higher rate of overall NRM (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.03-4.35; P = 04) and 1-year incidence of infection (HR, 2.63; 95% CI, 1.54-4.55; P < .001) in addition to a significantly lower 2-year survival (P = .019). Kidney function estimated via estimated GFR (eGFR) and estimated creatinine clearance did not correlate with posttransplant outcomes. These results suggest that mGFR is a promising approach for assessing clearance in patients who have undergone allogeneic HSCT and may be preferred to standard creatinine-based eGFR strategies.
Topics: Creatinine; Graft vs Host Disease; Humans; Iothalamic Acid; Melphalan; Retrospective Studies; Vidarabine
PubMed: 35522968
DOI: 10.1182/bloodadvances.2021006395 -
Japanese Journal of Ophthalmology Jul 2020To evaluate clinical outcomes and enucleation rates after intravitreal melphalan (IVM) alone and after IVM combined with intravitreal topotecan (IVT) for the treatment... (Comparative Study)
Comparative Study
PURPOSE
To evaluate clinical outcomes and enucleation rates after intravitreal melphalan (IVM) alone and after IVM combined with intravitreal topotecan (IVT) for the treatment of vitreous disease, and to a lesser extent subretinal and retrohyaloid seeds, in patients with retinoblastoma.
STUDY DESIGN
A retrospective analysis of 77 eyes of 72 consecutive patients.
METHODS
Demographic data, classification of tumors, seed type (dust, sphere or cloud) before injection and at the end of follow-up, injection type (IVM or IVM+IVT), doses of IVM and IVT, number of injections, follow-up time, enucleation status and side effects were recorded. Cox regression analysis and log-rank test for Kaplan-Meier curves were performed.
RESULTS
Of 77 eyes, 40 received IVM alone (group 1) and 37 received IVM+IVT (group 2). Enucleation rates were 62.5% (n=25) in group 1 and 10.8% (n=4) in group 2 (p=0.001). Median eye survival was 23.6 months in group 1 and 25.6 months in group 2. Mantel-Cox test revealed statistically significant differences between Kaplan-Meier curves of group 1 and 2 (p=0.022). Multiple Cox regression analysis showed a significantly elevated enucleation rate associated with: IVM only treatment group (p=0.019) and pre-injection cloud type of seeding (p=0.014).
CONCLUSION
The combined use of intravitreal melphalan and topotecan provides significantly better results in terms of avoiding enucleation and vitreal and subretinal seed control.
Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Drug Therapy, Combination; Eye Diseases; Eye Enucleation; Female; Follow-Up Studies; Humans; Infant; Intravitreal Injections; Kaplan-Meier Estimate; Male; Melphalan; Neoplasm Seeding; Proportional Hazards Models; Retinal Diseases; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topoisomerase I Inhibitors; Topotecan; Treatment Outcome; Vitreous Body
PubMed: 32447585
DOI: 10.1007/s10384-020-00743-2 -
British Journal of Clinical Pharmacology Jan 2022We studied melphalan pharmacokinetics (PK) and feasibility of melphalan full-dose adjustment based on test-dose PK in children and young adults with non-malignant...
AIMS
We studied melphalan pharmacokinetics (PK) and feasibility of melphalan full-dose adjustment based on test-dose PK in children and young adults with non-malignant disorders (NMD) undergoing allogeneic hematopoietic cell transplantation (HCT) using reduced intensity conditioning (RIC) containing alemtuzumab, fludarabine and melphalan.
METHODS
Patients received test-dose melphalan (10% of planned full-dose) prior to conditioning. Blood samples for PK were obtained around test and full-dose melphalan (140 mg/m or 4.7 mg/kg in patients <10 kg). Melphalan concentration was measured by liquid chromatography electrospray ionization tandem mass-spectrometry assay and data were analysed using a population-PK model and Bayesian estimation. Test and full-dose melphalan clearance estimates were evaluated by pairwise Wilcoxon test and Bland-Altman plot.
RESULTS
Twenty-four patients undergoing 25 transplants were included in the final analysis. Patients received standard full-dose melphalan in 17 transplants, with median area under the concentration-time curve (AUC) of 5.5 mg*h/L (range, 3.0-9.5 mg*h/L). Patients received test-dose melphalan in 23 transplants with a test-dose PK predicted full-dose AUC range of 2.9-16.8 mg*h/L. In seven transplants where patients had baseline organ impairment, test-dose PK predicted higher exposure for standard full-dose (median AUC 13.8 mg*h/L). Melphalan full-dose was adjusted in these patients, with achievement of desired target AUC (3.6-5.4 mg*h/L) and no excess toxicity. Mean ratio of test-dose clearance to full-dose clearance was 1.03. Twenty of 22 patients (91%) were within the 95% confidence intervals of the clearance ratio.
CONCLUSION
Melphalan test-dose PK reliably predicts full-dose PK and allows for accurate adjustment of full-dose melphalan in RIC-HCT for NMD. This approach can avoid excess toxicity from increased systemic exposure, especially in patients with organ impairment.
Topics: Bayes Theorem; Child; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Young Adult
PubMed: 34075614
DOI: 10.1111/bcp.14932 -
International Journal of Pharmaceutical... 2020Melphalan is used in selective ophthalmic artery infusion chemotherapy. In the procedure to catheterize the ophthalmic artery in selective ophthalmic artery infusion...
Melphalan is used in selective ophthalmic artery infusion chemotherapy. In the procedure to catheterize the ophthalmic artery in selective ophthalmic artery infusion chemotherapy, the microcatheter is usually filled with an iodinated contrast medium. It is not known whether mixing of iodinated contrast medium with melphalan solutions promotes precipitation of melphalan during selective ophthalmic artery infusion chemotherapy. The objective of the present study was to examine the compatibility of melphalan and iodinated contrast medium. In the experiments, melphalan solutions were prepared with and without iodinated contrast medium (iohexol 300 mg Iodine/mL or ioversol 74%). Melphalan solution of clinically relevant concentration (0.45 mg/mL) in the absence of iodinated contrast medium was evaluated as a reference. The 0.45-mg/mL melphalan solution was diluted with iodinated contrast medium at 1:9 and 1:1 ratios to form solutions comprising iodinated contrast medium at 10% or 50% (v/v), and each was evaluated. The formation of particles was examined using filtration (pore size 0.45 µm) followed by high-performance liquid chromatography at four quarterly time intervals (15 min, 30 min, 45 min, and 60 min) over a 1-hour period after solution preparation. High-performance liquid chromatography analysis of microfiltered solutions did not reveal evidence of melphalan crystal formation over a 60-minute period for the solutions studied. The filtration studies suggest that mixing of the iodinated contrast medium with melphalan solutions does not result in significant melphalan precipitation.
Topics: Contrast Media; Iodine; Iohexol; Melphalan; Ophthalmic Artery
PubMed: 32023220
DOI: No ID Found -
Die Anaesthesiologie Feb 2023Percutaneous hepatic melphalan perfusion (PHMP) is a last-line treatment of inoperable primary or secondary liver tumors. Selective perfusion and saturation... (Review)
Review
Percutaneous hepatic melphalan perfusion (PHMP) is a last-line treatment of inoperable primary or secondary liver tumors. Selective perfusion and saturation (chemosaturation) of the liver with the chemotherapeutic agent melphalan is performed via catheterization of the hepatic artery without affecting the rest of the body with its cytotoxic properties. Using an extracorporeal circulation and balloon occlusion of the inferior vena cava, the venous hepatic blood is filtered and returned using a bypass procedure. During the procedure, considerable circulatory depression and coagulopathy are frequent. The purpose of this article is to review the anesthesiological and postprocedural management of patients undergoing PHMP with consideration of the pitfalls and special circumstances.
Topics: Humans; Melphalan; Chemotherapy, Cancer, Regional Perfusion; Antineoplastic Agents; Extracorporeal Circulation; Perfusion
PubMed: 36477906
DOI: 10.1007/s00101-022-01235-3 -
Medicina 2022Immunoglobulin light chain (AL) amyloidosis is a rare disease. Treatment is challenging, justified in part by systemic compromise and limited scientific evidence.
INTRODUCTION
Immunoglobulin light chain (AL) amyloidosis is a rare disease. Treatment is challenging, justified in part by systemic compromise and limited scientific evidence.
OBJECTIVES
Develop evidencebased recommendations that allow adequate treatment of patients with amyloidosis AL.
METHODS
A list of PICO format questions focused on the effectiveness and safety of amyloidosis AL treatment was generated. PubMed, Cochrane and Epistemonikos were searched. The levels of evidence and grades of recommendation were based on the GRADE system.
RESULTS
11 recommendations were generated. In selected patients with amyloidosis AL, autologous hematopoietic stem cell transplantation (ASCT) is recommended after induction with bortezomibbased regimens and conditioning with melphalan, since it could deepen the hematological and organ response, its durability and improve survival. In patients not eligible for ASCT, first-line treatment with bortezomib-based regimens is recommended, since it is likely to achieve a higher rate of hematological and organ response and improve survival. In patients with a contraindication or inaccessibility to bortezomib, treatment with alkylating agents and corticosteroids is recommended, since they are likely to achieve haematological and organ response and improve survival.
DISCUSSION
These treatment recommendations are based on the available evidence and the experience of the panel of experts, in a scenario of limited available resources, according to developing countries.
Topics: Amyloidosis; Bortezomib; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Transplantation, Autologous; Treatment Outcome
PubMed: 35904916
DOI: No ID Found -
Blood Apr 2023High-dose melphalan (HDM) improves progression-free survival in multiple myeloma (MM), yet melphalan is a DNA-damaging alkylating agent; therefore, we assessed its...
High-dose melphalan (HDM) improves progression-free survival in multiple myeloma (MM), yet melphalan is a DNA-damaging alkylating agent; therefore, we assessed its mutational effect on surviving myeloma cells by analyzing paired MM samples collected at diagnosis and relapse in the IFM 2009 study. We performed deep whole-genome sequencing on samples from 68 patients, 43 of whom were treated with RVD (lenalidomide, bortezomib, and dexamethasone) and 25 with RVD + HDM. Although the number of mutations was similar at diagnosis in both groups (7137 vs 7230; P = .67), the HDM group had significantly more mutations at relapse (9242 vs 13 383, P = .005). No change in the frequency of copy number alterations or structural variants was observed. The newly acquired mutations were typically associated with DNA damage and double-stranded breaks and were predominantly on the transcribed strand. A machine learning model, using this unique pattern, predicted patients who would receive HDM with high sensitivity, specificity, and positive prediction value. Clonal evolution analysis showed that all patients treated with HDM had clonal selection, whereas a static progression was observed with RVD. A significantly higher percentage of mutations were subclonal in the HDM cohort. Intriguingly, patients treated with HDM who achieved complete remission (CR) had significantly more mutations at relapse yet had similar survival rates as those treated with RVD who achieved CR. This similarity could have been due to HDM relapse samples having significantly more neoantigens. Overall, our study identifies increased genomic changes associated with HDM and provides rationale to further understand clonal complexity.
Topics: Humans; Multiple Myeloma; Melphalan; Neoplasm Recurrence, Local; Bortezomib; Lenalidomide; Antineoplastic Combined Chemotherapy Protocols; Chronic Disease; Transplantation, Autologous; Dexamethasone
PubMed: 36603186
DOI: 10.1182/blood.2022017094