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Transplantation and Cellular Therapy Jan 2023Single-agent, high-dose melphalan continues to be the most commonly used conditioning regimen for transplantation-eligible patients with multiple myeloma undergoing...
Single-agent, high-dose melphalan continues to be the most commonly used conditioning regimen for transplantation-eligible patients with multiple myeloma undergoing autologous stem cell transplantation. The timing of melphalan administration with respect to stem cell infusion has not been clearly defined. Many institutions require a minimum of 24 hours between melphalan administration and stem cell infusion; however, some institutions have adopted shorter intervals based on melphalan's short half-life. Some studies have suggested that shortening the interval between melphalan administration and stem cell infusion may contribute to delays in engraftment, but this correlation has not been clearly evaluated or defined. This multicenter retrospective cohort study evaluated the times to neutrophil and platelet engraftment in patients who received stem cells at least 24 hours after melphalan (≥24 hours cohort) compared with those who received stem cells within 24 hours of melphalan (<24 hours cohort. The study included a total of 723 adult patients, 502 patients in the ≥24 hours cohort and 221 in the <24 hours cohort, treated at 3 transplantation centers between January 1, 2016, and September 30, 2019. Patient characteristics were summarized using descriptive statistics. The Fisher exact test was used to compare nominal categorical variables between the 2 cohorts, and the nonparametric van der Waerden test or Mood median test was used to compare ordinal or continuous variables. The median time to neutrophil engraftment was 12 days for both the ≥24 hours cohort (interquartile range [IQR], 11 to 12 days) and the <24 hours cohort (IQR, 11 to 13 days) (P = .07). The median time to platelet engraftment was 19 days for both the ≥24 hours cohort (IQR, 17 to 22 days) and <24 hours cohort (IQR, 17 to 20 days) (P = .25). The median time between melphalan administration and stem cell infusion in the <24 hours cohort was 18 hours, with a minimum time of 12 hours. The existing literature has not clearly defined the impact of the timing between melphalan administration and stem cell infusion on engraftment in autologous transplantation. The ability to safely shorten the interval between chemotherapy and transplantation could increase logistical flexibility and/or decrease the length of hospital stay. This large multicenter retrospective study did not identify a statistical or clinical impact on engraftment when melphalan was infused <24 hours or ≥24 hours before autologous stem cell infusion.
Topics: Adult; Humans; Melphalan; Hematopoietic Stem Cell Transplantation; Retrospective Studies; Transplantation, Autologous
PubMed: 36404519
DOI: 10.1016/j.jtct.2022.10.017 -
Nucleic Acids Research Aug 2023Fanconi anemia (FA) is a genetic disorder associated with developmental defects, bone marrow failure and cancer. The FA pathway is crucial for the repair of DNA...
Fanconi anemia (FA) is a genetic disorder associated with developmental defects, bone marrow failure and cancer. The FA pathway is crucial for the repair of DNA interstrand crosslinks (ICLs). In this study, we have developed and characterized a new tool to investigate ICL repair: a clickable version of the crosslinking agent melphalan which we name click-melphalan. Our results demonstrate that click-melphalan is as effective as its unmodified counterpart in generating ICLs and associated toxicity. The lesions induced by click-melphalan can be detected in cells by post-labelling with a fluorescent reporter and quantified using flow cytometry. Since click-melphalan induces both ICLs and monoadducts, we generated click-mono-melphalan, which only induces monoadducts, in order to distinguish between the two types of DNA repair. By using both molecules, we show that FANCD2 knock-out cells are deficient in removing click-melphalan-induced lesions. We also found that these cells display a delay in repairing click-mono-melphalan-induced monoadducts. Our data further revealed that the presence of unrepaired ICLs inhibits monoadduct repair. Finally, our study demonstrates that these clickable molecules can differentiate intrinsic DNA repair deficiencies in primary FA patient cells from those in primary xeroderma pigmentosum patient cells. As such, these molecules may have potential for developing diagnostic tests.
Topics: Humans; Melphalan; Fanconi Anemia; DNA Repair; DNA Damage; DNA
PubMed: 37395445
DOI: 10.1093/nar/gkad559 -
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 -
Cell Transplantation 2023High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard of care for selected patients with refractory/relapsed Hodgkin's lymphoma... (Meta-Analysis)
Meta-Analysis
BeEAM (Bendamustine, Etoposide, Cytarabine, Melphalan) Versus BEAM (Carmustine, Etoposide, Cytarabine, Melphalan) as Conditioning Regimen Before Autologous Haematopoietic Cell Transplantation: A Systematic Review and Meta-Analysis.
High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard of care for selected patients with refractory/relapsed Hodgkin's lymphoma (HL) or non-Hodgkin's lymphoma (NHL), and it is also used as first-line clinical consolidation option for some aggressive NHL subtypes. Conditioning regimen prior to ASCT is one of the essential factors related with clinical outcomes post transplant. The conditioning regimen of carmustine, etoposide, cytarabine, and melphalan (BEAM) traditionally is considered the standard of care for patients with lymphoma who are eligible for transplantation. Replacement of carmustine with bendamustine (BeEAM) was described as an alternative conditioning regimen in the autograft setting for patients with lymphoma. Several studies have reported inconsistent clinical outcomes comparing BeEAM and BEAM. Therefore, in the lack of well-designed prospective comparative studies, the comparison of BeEAM versus BEAM is based on retrospective trials. To compare the clinical outcomes between BeEAM and BEAM, we performed a meta-analysis of 10 studies which compared the outcomes between BeEAM and BEAM in patients autografted for lymphoma disease (HL or NHL). We searched article titles and compared transplantation with BeEAM versus BEAM in MEDLINE (PubMed), Cochrane library, and EMBASE database. Here, we report the results of nine main endpoints in our meta-analysis comparing BeEAM and BEAM, including neutrophil engraftment (NE), platelet engraftment (PE), overall survival (OS), progression free survival (PFS), non-relapse mortality (NRM), relapse rate (RR), grade 3 mucositis, renal toxicity, and cardiotoxicity. We discovered that the BeEAM regimen was associated with a slightly better PFS [pooled odds ratio (OR) of 0.70, 95% confidence interval (CI), 0.52-0.94, = 0.02], lower RR (0.49, 95% CI, 0.31-0.76, = 0.002), higher mucositis (3.43, 95% CI, 2.29-5.16, = 0.001), renal toxicity (4.49, 95% CI, 2.68-7.51, = 0.001), and cardiotoxicity (1.88, 95% CI, 1.03-3.40, = 0.03). We also discovered that the two groups had equivalent NE (pooled WMD -0.64, 95% CI, -1.46 to 0.18, = 0.13), PE (pooled WMD -0.3, 95% CI, -1.68 to 2.28, = 0.77), OS (0.73, 95% CI, 0.52-1.01, = 0.07), and NRM (1.51, 95% CI, 0.76-2.98, = 0.24). The results of this meta-analysis show that the BeEAM regimen is a viable alternative to BEAM. More prospective comparisons between BeEAM and BEAM are required.
Topics: Humans; Carmustine; Transplantation, Autologous; Bendamustine Hydrochloride; Hematopoietic Stem Cell Transplantation; Cytarabine; Etoposide; Melphalan; Cardiotoxicity; Mucositis; Retrospective Studies; Neoplasm Recurrence, Local; Lymphoma, Non-Hodgkin
PubMed: 37350429
DOI: 10.1177/09636897231179364 -
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