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"An alkylating nitrogen mustard that is used as an antineoplastic in the form of the levo isomer - MELPHALAN, the racemic mixture - MERPHALAN, and the dextro isomer - MEDPHALAN; toxic to bone marrow, but little vesicant action; potential carcinogen." (MeSH 2013)

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Latest Research Publications

Web Resources: Melphalan (6 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Artzner C, Mossakowski O, Hefferman G, et al.
Chemosaturation with percutaneous hepatic perfusion of melphalan for liver-dominant metastatic uveal melanoma: a single center experience.
Cancer Imaging. 2019; 19(1):31 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To investigate the outcome and safety data of chemosaturation with percutaneous hepatic perfusion (CS-PHP) of melphalan in patients with liver-dominant metastatic uveal melanoma.
MATERIAL AND METHODS: This is a HIPAA compliant, IRB approved, retrospective study. A total of 28 CS-PHPs were performed in 16 individual patients (six men and ten women, median age 63.1 years [range 49.1 to 78.7 years], one to six CS-PHP procedures per patient) for treatment of liver-dominant metastatic uveal melanoma between June, 2015 and December, 2018. All patients received cross-sectional imaging at baseline and during follow-up. CS-PHP was performed with the Hepatic CHEMOSAT® Delivery System (Delcath Systems, Inc., NY, USA) facilitating extracorporeal filtration of hepatic blood for melphalan removal. Ideal body weight-adjusted melphalan doses were administered into the hepatic arteries. Serious adverse events (SAE), progression-free survival based on response criteria in solid tumors, and overall survival were noted. Survival data were analyzed using Kaplan-Meier estimates.
RESULTS: Partial response after first CS-PHP was observed in nine patients (60%), stable disease in five patients (33%) and progressive disease in one patient (7%). Median overall survival was 27.4 months (95% CI 4.1 to 35.4 month) after first CS-PHP. Median progression-free survival was 11.1 months after first CS-PHP (95% CI 4.9 to 23.6 months). SAEs were observed in the majority of patients with most SAEs limited to grades one and two. Thirteen SAEs of grades three and four were observed in seven individual patients. No grade five SAE was observed.
CONCLUSION: CS-PHP is an efficacious and safe treatment for patients presenting with liver-dominant metastatic uveal melanoma.

Cho SH, Shin HJ, Jung KS, Kim Y
Dose Adjustment Helps Obtain Better Outcomes in Multiple Myeloma Patients with Bortezomib, Melphalan, and Prednisolone (VMP) Treatment
Turk J Haematol. 2019; 36(2):106-111 [PubMed] Free Access to Full Article Related Publications
Objective: Multiple myeloma (MM) has a better survival outcome because of the development of drugs. However, equivalent outcomes cannot be expected from the same drug. Therefore, how the treatment schedule is managed is important. We analyzed VMP (bortezomib, melphalan, and prednisolone) data to determine an effective treatment strategy.
Materials and Methods: We collected the data of 59 patients who were newly diagnosed with MM from January 2012 to April 2017 using electronic medical records. We analyzed baseline characteristics, responses, dose reductions, and survival.
Results: The overall response rate was 86.5% [complete response (CR): 32.2%, very good partial response (VGPR): 37.3%]. The median progression-free survival was 33.6 months and the 5-year overall survival rate was 70%. There were significant better progression-free survival outcomes between CR and non-CR for each of the 4 cycles. Of the four patients who achieved CR after the first cycle, none have had disease progression as of yet. We divided patients into two groups according to the median dose (52.1 mg/m
Conclusion: Active dose reduction helped to continue treatment and it increased the opportunity to be exposed to drugs. In the end, it resulted in improved outcome.

Chung A, Liedtke M
Therapy-related myeloid neoplasms after treatment for plasma-cell disorders.
Best Pract Res Clin Haematol. 2019; 32(1):54-64 [PubMed] Related Publications
Therapy-related myeloid neoplasms (t-MN), including therapy-related acute myeloid leukaemia and myelodysplastic syndrome, are second primary malignancies (SPM) that are of growing importance as patients with plasma cell disorders (PCD) such as multiple myeloma (MM) are living longer with more effective therapies. Both patient-specific and treatment-specific factors likely impact the risk of t-MN development after diagnosis and treatment of PCD. Alkylating chemotherapy, especially melphalan, has been strongly tied to the risk of t-MN. More recently, there has been a shift away from long-term alkylating therapies to immunomodulatory agents and high-dose therapy with autologous stem cell transplant (HD-ASCT). This shift has led to improved survival and long-term outcomes for most MM patients. However, the risks of t-MN remain despite the improved efficacy of these treatments, and patients who develop t-MN have a poor prognosis. Understanding the risk factors predisposing MM patients to t-MN can thus help to tailor individualized therapy to maximize anti-myeloma efficacy and minimize the risks of t-MN.

Daniels AB, Froehler MT, Nunnally AH, et al.
Rabbit Model of Intra-Arterial Chemotherapy Toxicity Demonstrates Retinopathy and Vasculopathy Related to Drug and Dose, Not Procedure or Approach.
Invest Ophthalmol Vis Sci. 2019; 60(4):954-964 [PubMed] Free Access to Full Article Related Publications
Purpose: To use our intra-arterial chemotherapy (IAC) rabbit model to assess the impact of IAC procedure, drug, dose, and choice of technique on ocular structure and function, to study the nature and etiology of IAC toxicity, and to compare to observations in patients.
Methods: Rabbits received IAC melphalan (0.4-0.8 mg/kg), carboplatin (25-50 mg), or saline, either by direct ophthalmic artery cannulation, or with a technique emulating nonocclusion. Ocular structure/function were assessed with examination, electroretinography (ERG), fundus photography, fluorescein angiography, optical coherence tomography (OCT), and OCT angiography, prior to and 5 to 6 weeks after IAC. Blood counts were obtained weekly. We reviewed our last 50 IAC treatments in patients for evidence of ocular or systemic complications.
Results: No toxicity was seen in the saline control group. With standard (0.4 mg/kg) melphalan, no vascular/microvascular abnormalities were seen with either technique. However, severe microvascular pruning and arteriolar occlusions were seen occasionally at 0.8 mg/kg doses. ERG reductions were dose-dependent. Histology showed melphalan dose-dependent degeneration in all retinal layers, restricted geographically to areas of greatest vascular density. Carboplatin caused massive edema of ocular/periocular structures. IAC patients experienced occasional periocular swelling/rash, and only rarely experienced retinopathy or vascular events/hemorrhage in eyes treated multiple times with triple (melphalan/carboplatin/topotecan) therapy. Transient neutropenia occurred after 46% of IAC procedures, generally after triple therapy.
Conclusions: IAC toxicity appears to be related to the specific drug being used and is dose-dependent, rather than related to the IAC procedure itself or the specific technique selected. These rabbit findings are corroborated by our clinical findings in patients.

Fujino H, Ishida H, Iguchi A, et al.
High rates of ovarian function preservation after hematopoietic cell transplantation with melphalan-based reduced intensity conditioning for pediatric acute leukemia: an analysis from the Japan Association of Childhood Leukemia Study (JACLS).
Int J Hematol. 2019; 109(5):578-583 [PubMed] Related Publications
Women are at high risk of hypergonadotropic hypogonadism after hematopoietic cell transplantation (HCT). Hypogonadism is universal after irradiation or busulfan. We hypothesized that reduced intensity conditioning (RIC) might protect ovarian function after HCT. We retrospectively reviewed data from patients with acute leukemia treated according to the Japan Association of Childhood Leukemia Study and nationwide multicenter study protocol. We selected 11 female patients with acute leukemia who received first HCT with RIC, had survived for three or more years after HCT, and were aged ≥ 12 years at the last follow-up visit. Median age at diagnosis, HCT, and last visit were 8, 10, and 17 years. Six patients received HLA-matched bone marrow (BM), two HLA-mismatched BM, and three cord blood. Melphalan was used as conditioning regimen in all patients. At the last visit, six of seven post-pubertal patients at transplantation recovered menstruation, and four of four patients who underwent transplantation at the pre-pubertal began menstruation. Height z scores showed no significant reduction between pre-transplant and post-transplant. No patients received growth hormone treatment. Only one recipient displayed subclinical hypothyroidism. Melphalan-based RIC may be an encouraging option for patients with acute leukemia to avoid ovarian and endocrine dysfunction after HCT.

Xue K, Ren H, Meng F, et al.
Ocular toxicity of intravitreal melphalan for retinoblastoma in Chinese patients.
BMC Ophthalmol. 2019; 19(1):61 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To evaluate the efficacy, complications, and clinical characteristics, including the ocular toxicity, of intravitreal melphalan(IVM) treatment for vitreous seeding in Chinese retinoblastoma patients.
METHODS: This was a retrospective, non-comparative analysis including 30 consecutive eyes of 23 patients with viable persistent or recurrent vitreous seeding following retinoblastoma treatment. All of the eyes received IVM injections (20-33 μg). Vitreous seeding control, determination of the ocular toxicity, and the clinical characteristics of intravitreal melphalan treatments were observed.
RESULTS: The mean patient age at the time of the injection was 28 months (median = 22 months, range = 12-50 months). In total, 80 injections were administered in 30 eyes, the overall enucleation-free survival rate was 83.3% (25/30). The complications included retinal pigment epithelium (RPE) and choroidal atrophy (19/30, 63.3%), pupillary synechiae (13/30, 43.3%), iris atrophy (12/30, 40%), retinal vascular occlusion (12/30, 40.0%), optic atrophy (6/30, 20%), vitreous hemorrhage (3/30, 10%), persistent hypotonia and phthisis bulbi (4/30 13.3%), and cataracts (8/30, 26.6%). Twelve eyes demonstrated grade 3 or greater IVM-associated retinal or anterior segment toxicity post injection. Mean dosage given showed significant difference between the groups. There were no significant differences in the retinal toxicity grades regarding the seed classification or seed regression patterns.
CONCLUSIONS: Intravitreal melphalan is an effective treatment for refractory vitreous seeding from retinoblastoma, but exhibits both anterior and posterior segment toxicity in Chinese patients.

Meijer TS, Burgmans MC, Fiocco M, et al.
Safety of Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Liver Metastases from Ocular Melanoma Using the Delcath Systems' Second-Generation Hemofiltration System: A Prospective Non-randomized Phase II Trial.
Cardiovasc Intervent Radiol. 2019; 42(6):841-852 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To investigate the safety and toxicity of percutaneous hepatic perfusion with melphalan (M-PHP) with the Delcath Systems' second-generation (GEN 2) filter and compare the outcomes with historical data from studies using the first-generation filter.
MATERIALS AND METHODS: A prospective, single-arm, single-center phase II study was carried out including 35 patients with unresectable, histologically confirmed liver metastases from ocular melanoma between February 2014 and June 2017. Main exclusion criteria were extrahepatic disease and age > 75 years. M-PHP was performed with melphalan 3 mg/kg (maximum dose 220 mg). Safety and toxicity were assessed according to the Common Terminology Criteria for Adverse Events version 4.03.
RESULTS: A total of 67 M-PHPs were performed in 35 patients (median 2 procedures). Although hematologic grade 3/4 events were seen in the majority of patients (thrombocytopenia 54.5%, leukopenia 75.6%, neutropenia 66.7%, anemia (only grade 3) 18.1%), these were all well manageable or self-limiting. Of the non-hematologic grade 3 events (n = 14), febrile neutropenia (n = 3), pulmonary emboli (n = 2) and post-procedural hemorrhage (n = 2) were most common. A case of sepsis with bacterial pharyngitis was the only non-hematologic grade 4 event. Prior therapy for liver metastases was found to be a predictor of late grade 3/4 neutropenia with an odds ratio of 5.5 (95% CI 1.4-21.7).
CONCLUSIONS: M-PHP using the GEN 2 filter has an acceptable safety and toxicity profile, and seems to reduce hematologic toxicity when compared to M-PHP with a first-generation filter. Prior therapy of liver metastases is a possible predictive factor in developing grade 3/4 hematologic toxicity.

Hoshino T, Takada S, Hatsumi N, Sakura T
Feasibility of salvage cord blood transplantation using a fludarabine, melphalan, and low-dose anti-thymocyte globulin conditioning regimen.
Int J Hematol. 2019; 109(4):463-469 [PubMed] Related Publications
Primary graft failure (PGF) is a lethal complication that occurs early after allogeneic stem cell transplantation (allo-SCT). Cord blood transplantation (CBT) is a potential re-transplantation option. Total body irradiation (TBI) is often incorporated into the pre-salvage CBT conditioning regimen following PGF; however, patients experiencing PGF are not always amenable to TBI, and non-TBI regimens for salvage CBT should be established. Here, we report five patients with hematologic malignancies who received salvage CBT for PGF following a non-TBI regimen using fludarabine (Flu), melphalan (Mel), and low-dose anti-thymocyte globulin (ATG). The median intervals between the failed allo-SCT and salvage CBT, as well as between the diagnosis of PGF and salvage CBT, were 37 days and 8 days, respectively. The median neutrophil recovery period was 21 days (range 18-21 days). Four of five patients achieved neutrophil engraftment following salvage CBT; all four exhibited sustained engraftment with complete donor chimerism. Three of the five patients were alive after a median follow-up time of 907 days (range 315-909 days) post-salvage CBT; two patients died of causes unrelated to recurrence. These data suggest that CBT following the non-TBI regimen described here is feasible in patients with PGF.

Rojanaporn D, Chanthanaphak E, Boonyaopas R, et al.
Intra-Arterial Chemotherapy for Retinoblastoma: 8-Year Experience from a Tertiary Referral Institute in Thailand.
Asia Pac J Ophthalmol (Phila). 2019 May-Jun; 8(3):211-217 [PubMed] Related Publications
PURPOSE: To study the safety and efficacy of intra-arterial chemotherapy (IAC) as a treatment for intraocular retinoblastoma in Thailand.
DESIGN: Retrospective, interventional case series.
METHODS: In this study, IAC was performed as primary or secondary treatment for patients with intraocular retinoblastoma using melphalan with or without additional topotecan or carboplatin. Survival rate, globe salvage rate, and treatment complications were recorded and analyzed.
RESULTS: Of 27 eyes of 26 patients with retinoblastoma, 7 (26%) had IAC as primary treatment and 20 (74%) had IAC as secondary treatment. The eyes were classified by International Classification of Retinoblastoma (ICRB) as group B (n = 3, 11%), group C (n = 1, 4%), group D (n = 12, 44%), and group E (n = 11, 41%). Catheterization was successful in 75 (94%) of 80 sessions. The median number of IAC sessions was 3 (range, 1-7). At a mean follow-up of 32 months (range, 3-95 months), the overall globe salvage rate was 52%, with 100% in groups B and C, 75% in group D, and 9% in group E. Complications of IAC included occlusive vasculopathy (n = 4, 15%), vitreous hemorrhage (n = 3, 11%), retinal artery precipitation (n = 2, 7%), strabismus (n = 2, 7%), and transient ischemic attack (n = 1, 4%). The overall survival rate was 96% (n = 25).
CONCLUSIONS: Our experience suggests that IAC is a safe and effective treatment for patients with ICRB group B, C, D, and some group E retinoblastoma. Careful patient selection and experienced surgeons are critical for achieving the best treatment outcome.

Stenzel E, Göricke S, Temming P, et al.
Feasibility of intra-arterial chemotherapy for retinoblastoma: experiences in a large single center cohort study.
Neuroradiology. 2019; 61(3):351-357 [PubMed] Related Publications
PURPOSE: In the last 10 years, intra-arterial chemotherapy (IAC) has been increasingly used in the clinical management of retinoblastoma. It is reported to provide tumor control even in advanced stage disease that might have previously required enucleation. In our clinical experience, there are three conditions that may impair the use of IAC: (1) significant collaterals to meningeal arteries, (2) technical failure of ophthalmic artery catheterization, or (3) retina blood supply from collaterals different to the ophthalmic artery. In the current study, we assessed the rate of IACs that could not be carried out in our institution due to these three reasons.
METHODS: All patients admitted for IAC in our hospital were retrospectively assessed by chart review. Non-application rate of IAC was assessed and classified according to the three abovementioned criteria. Complication rate of both finalized and interrupted interventions was recorded.
RESULTS: Ninety-eight patients (median age 21.4 months, range 5.3 months-10.5 years) were identified. IAC was performed in 69 (70.4%) patients and interrupted in 12 (12.2%) cases because of meningeal collaterals, in 8 (8.2%) because of technical failure to cannulate the ophthalmic artery, and in 9 (9.2%) because of alternative blood supply of the retina.
CONCLUSION: The rather defensive approach that is pursued in our center resulted in an overall non-application rate of IAC around 30%. The relatively high probability of conditions that impair the use of IAC needs to be addressed adequately in the patient conversation prior to the procedure. Our rate of 8% of abstention from IAC due to technical limitations might be reduced by the application of more rigorous therapeutic approaches such as balloon occlusion of the distal internal carotid artery. More research is finally needed to determine if IAC can be safely performed in the presence of meningeal collaterals and via branches of the external carotid artery.

Sipok A, Sardi A, Nieroda C, et al.
Comparison of Survival in Patients with Isolated Peritoneal Carcinomatosis from Colorectal Cancer Treated with Cytoreduction and Melphalan or Mitomycin-C as Hyperthermic Intraperitoneal Chemotherapy Agent.
Int J Surg Oncol. 2018; 2018:1920276 [PubMed] Free Access to Full Article Related Publications
Background: The role of hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is debated. Melphalan as a perfusion agent has also demonstrated survival benefit in other recurrent and chemoresistant malignancies. Thus, we hypothesize that melphalan as a HIPEC agent may improve overall survival (OS) and progression-free survival (PFS) in patients with PC from CRC.
Methods: A retrospective review of a prospective database of 48 patients who underwent optimal CRS (CC-0/1) and HIPEC from 2001-2016 was performed. Nineteen had CRS/HIPEC with melphalan (group I) and 29 with mitomycin-C (group II). Survival was estimated using the Kaplan-Meier method. Cox regression was used for multivariate analysis. Perioperative variables were compared.
Results: Mean age at CRS/HIPEC was 53±10 years. Median peritoneal cancer index (PCI) was 17 vs 13 in groups I and II, respectively (p=0.86). PCI≥20 occurred in 9 (47%) and 13 (45%) patients in groups I and II, respectively. Positive lymph nodes were identified in 8/19 (42%) vs 12/29 (41%) in groups I and II, respectively (p=0.73). Multivariate analysis identified PCI≥20 as a predictive factor of survival (HR: 7.5). Median OS in groups I and II was 36 and 28 months, respectively (p=0.54). Median PFS in groups I and II was 10 and 20 months, respectively (p=0.05).
Conclusions: CRS/HIPEC with MMC had longer median PFS in PC from CRC. PCI≥20 was the only independent predictive factor for survival. Until longer follow-up is available, we recommend using MMC in CRS/HIPEC for PC from CRC. Further prospective randomized studies are necessary.

Belgrano V, Pettersson J, Nilsson JA, et al.
Response and Toxicity of Repeated Isolated Limb Perfusion (re-ILP) for Patients With In-Transit Metastases of Malignant Melanoma.
Ann Surg Oncol. 2019; 26(4):1055-1062 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Isolated limb perfusion (ILP) is a safe and well-established treatment for in-transit metastases of melanoma. In case of relapse or disease progression, ILP can be repeated (re-ILP). This study aimed retrospectively to analyze a large consecutive series of re-ILP and compare clinical outcomes with first-time ILP.
METHOD: Between 2001 and 2015, 290 consecutive patients underwent 380 ILPs. Of these, 90 were re-ILPs including 68 second ILPs, 16 third ILPs, 4 fourth ILPs, and two fifth ILPs. The study evaluated response (using World Health Organization [WHO] criteria), local toxicity (using the Wieberdink scale), and complications (using Clavien-Dindo).
RESULTS: The results were compared between the first ILP, the second ILP, and the third to fifth ILP. The overall response rate was respectively 83%, 80% and 68%, with a complete response (CR) rate of 60%, 41%, and 59%. In the re-ILP group, the patients with a CR after the first ILP had a 65% CR rate after the second ILP compared with 8% for the patients without a CR (p = 0.001). The risk for local toxicity or complications was not increased after re-ILP. The median overall survival periods were respectively 34, 41, and 93 months (p = 0.02).
CONCLUSION: As a therapeutic option, ILP can be repeated safely for in-transit metastases of melanoma, achieving similar high response rates without increasing complications or toxicity. Re-ILP is mainly indicated for patients who already had a CR after the first ILP, whereas other treatment options should be considered for primary non-responders.

Poi MJ, Li J, Johnson JA, et al.
A Single Nucleotide Polymorphism in
Anticancer Res. 2019; 39(1):67-72 [PubMed] Related Publications
BACKGROUND/AIM: SLC7A5 is recognized as the major mediator of melphalan uptake into multiple myeloma (MM) cells; however, its contribution to the inter-patient variability of melphalan efficacy and toxicity is yet to be well elucidated. This study aimed to investigate the impact of a single nucleotide polymorphism (SNP) rs4240803 in SLC7A5 on the gene expression, ex vivo sensitivity to melphalan, and clinical outcomes in MM patients who were undergoing autologous stem cell transplantation with high-dose melphalan.
MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMC) were collected from 108 MM patients prior to melphalan therapy. Clinical data were also collected from these patients following melphalan therapy.
RESULTS: rs4240803 was associated with elevated expression of SLC7A5 mRNA, higher ex vivo sensitivity to melphalan in PBMCs, and positive 90-day response in these patients (p=0.047, 0.10, 0.049, respectively).
CONCLUSION: rs4240803 impacted the expression of SLC7A5, thus contributing to the clinical response of MM patients to melphalan therapy.

Tendas A, Marchesi F, Mengarelli A, et al.
Prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan and stem cell transplantation: review of the evidence and suggestions.
Support Care Cancer. 2019; 27(3):793-803 [PubMed] Related Publications
INTRODUCTION: High-dose melphalan (HDMel) is the most common conditioning chemotherapy regimen for autologous stem cell transplantation (SCT) in patients affected by multiple myeloma (MM). No consensus exists for the emetogenicity or prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in this regimen.
METHODS: Data on the incidence and efficacy/safety of CINV prophylaxis among patients affected by MM undergoing autologous SCT with the HDMel regimen was extracted from electronic databases and analyzed.
RESULTS: Eleven studies involving multiple CINV prophylaxis regimens were identified and included. No consensus on HDMel emetogenicity was reached, but most studies summarized the emetogenicity as moderate-high risk. An aprepitant-based three-drug regimen (aprepitant + serotonin receptor antagonist (5HT3RA) + dexamethasone) showed better efficacy than a two-drug regimen (5HT3RA + dexamethasone) for CINV prevention without increasing the frequency in adverse events.
CONCLUSIONS: The aprepitant-based three-drug regimen should be the regimen of choice for CINV prophylaxis for MM patients undergoing autologous SCT with HDMel conditioning.

Ueda T, Maeda T, Kusakabe S, et al.
Addition of melphalan to fludarabine/busulfan (FLU/BU4/MEL) provides survival benefit for patients with myeloid malignancy following allogeneic bone-marrow transplantation/peripheral blood stem-cell transplantation.
Int J Hematol. 2019; 109(2):197-205 [PubMed] Related Publications
A conditioning regimen with fludarabine and myeloablative dose of busulfan (FLU/BU4) has been commonly used in allogeneic hematopoietic cell transplantation (allo-HCT). However, there are two major problems with this regimen: insufficient anti-leukemic effect, especially in advanced cases, and slow time to complete donor-type chimerism, especially T-cell chimerism. To overcome these issues, we designed a combination regimen with FLU (150 mg/m

Tsubaki M, Takeda T, Tomonari Y, et al.
Overexpression of HIF-1α contributes to melphalan resistance in multiple myeloma cells by activation of ERK1/2, Akt, and NF-κB.
Lab Invest. 2019; 99(1):72-84 [PubMed] Related Publications
Multiple myeloma (MM) commonly displays multidrug resistance and is associated with poor prognosis. Therefore, it is important to identify the mechanisms by which MM cells develop multidrug resistance. Our previous study showed that multidrug resistance is correlated with overexpression of multidrug resistance protein 1 (MDR1) and Survivin, and downregulation of Bim expression in melphalan-resistant RPMI8226/L-PAM cells; however, the underlying mechanism of multidrug resistance remains unclear. In the present study, we investigated the mechanism of multidrug resistance in melphalan-resistant cells. We found that RPMI8226/L-PAM and ARH-77/L-PAM cells showed increased phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and Akt, and nuclear localization of nuclear factor κB (NF-κB). The combination of ERK1/2, Akt, and NF-κB inhibitors with melphalan reversed melphalan resistance via suppression of Survivin expression and enhanced Bim expression in melphalan-resistant cells. In addition, RPMI8226/L-PAM and ARH-77/L-PAM cells overexpressed hypoxia-inducible factor 1α (HIF-1α) via activation of ERK1/2, Akt, and NF-κB. Moreover, suppression of HIF-1α by echinomycin or HIF-1α siRNA resensitized RPMI8226/L-PAM cells to melphalan through downregulation of Survivin expression and upregulation of Bim expression. These results indicate that enhanced Survivin expression and decreased Bim expression by HIF-1α via activation of ERK1/2, Akt, and NF-κB play a critical role in melphalan resistance. Our findings suggest that HIF-1α, ERK1/2, Akt, and NF-κB inhibitors are potentially useful as anti-MDR agents for the treatment of melphalan-resistant MM.

Wang L, Han M, Zhao J, et al.
Intra-arterial chemotherapy for unilateral advanced intraocular retinoblastoma: Results and short-term complications.
Medicine (Baltimore). 2018; 97(42):e12676 [PubMed] Free Access to Full Article Related Publications
Intra-arterial chemotherapy (IAC) has become an essential technique for the management of advanced intraocular retinoblastoma (RB). In this study, the aim of this article is to describe the clinical results and the short-term complications of IAC performed in our hospital.We retrospectively analyzed patients with newly diagnosed unilateral advanced intraocular (group D or E) RB undergoing IAC from October 2016 to December 2017 in our hospital. We recorded the data including age, gender, cycles of IAC, pathway of arteries approached (ophthalmic artery or middle meningeal artery), ocular and systematic complications, globe salvage.Sixty-one patients underwent IAC performing 189 procedures with a median of 3.1 sessions per eye (range, 1-5 sessions). The overall globe salvage rate is 78.7% (Group D (84.2%), and Group E (69.6%) and followed-up. Short-term ocular complications include eyelid edema (15 cases), ptosis (5 cases), forehead congestion (3 cases), retina hemorrhage (5 cases), choroid atrophy (2 cases), phthisis bulbi (1 case), bradycardia and hypotension during the procedure (7cases), myelosuppressions (6 cases), and nausea and vomiting (5cases).IAC is safe and effective for the treatment of unilateral advanced intraocular RB with a very low complication rate.

Wu C, Nilsson K, Zheng Y, et al.
Short half-life of HPV16 E6 and E7 mRNAs sensitizes HPV16-positive tonsillar cancer cell line HN26 to DNA-damaging drugs.
Int J Cancer. 2019; 144(2):297-310 [PubMed] Free Access to Full Article Related Publications
Here we show that treatment of the HPV16-positive tonsillar cancer cell line HN26 with DNA alkylating cancer drug melphalan-induced p53 and activated apoptosis. Melphalan reduced the levels of RNA polymerase II and cellular transcription factor Sp1 that were associated with HPV16 DNA. The resulting inhibition of transcription caused a rapid loss of the HPV16 early mRNAs encoding E6 and E7 as a result of their inherent instability. As a consequence of HPV16 E6 and E7 down-regulation, the DNA damage inflicted on the cells by melphalan caused induction of p53 and activation of apoptosis in the HN26 cells. The BARD1-negative phenotype of the HN26 cells may have contributed to the failure to repair DNA damage caused by melphalan, as well as to the efficient apoptosis induction. Finally, nude mice carrying the HPV16 positive tonsillar cancer cells responded better to melphalan than to cisplatin, the chemotherapeutic drug of choice for tonsillar cancer. We concluded that the short half-life of the HPV16 E6 and E7 mRNAs renders HPV16-driven tonsillar cancer cells particularly sensitive to DNA damaging agents such as melphalan since melphalan both inhibits transcription and causes DNA damage.

Marquardt S, Kirstein MM, Brüning R, et al.
Percutaneous hepatic perfusion (chemosaturation) with melphalan in patients with intrahepatic cholangiocarcinoma: European multicentre study on safety, short-term effects and survival.
Eur Radiol. 2019; 29(4):1882-1892 [PubMed] Related Publications
OBJECTIVES: Cholangiocarcinoma is the second most common primary liver tumour with a poor overall prognosis. Percutaneous hepatic perfusion (PHP) is a directed therapy for primary and secondary liver malignancies, and its efficacy and safety have been shown in different entities. The purpose of this study was to prove the safety and efficacy of PHP in patients with unresectable intrahepatic cholangiocarcinoma (iCCA).
PATIENTS AND METHODS: We retrospectively reviewed data from 15 patients with unresectable iCCA treated with PHP in nine different hospitals throughout Europe. Overall response rates (ORR) were assessed according to response evaluation criteria in solid tumours (RECIST1.1). Overall survival (OS), progression-free survival (PFS) and hepatic PFS (hPFS) were analysed using the Kaplan-Meier estimation. Adverse events (AEs) and toxicity were evaluated.
RESULTS: Fifteen patients were treated with 26 PHPs. ORR was 20%, disease control was achieved in 53% after the first PHP. Median OS was 26.9 months from initial diagnosis and 7.6 months from first PHP. Median PFS and hPFS were 122 and 131 days, respectively. Patients with liver-only disease had a significantly longer median OS compared to patients with locoregional lymph node metastases (12.9 vs. 4.8 months, respectively; p < 0.01). Haematological toxicity was common, but manageable. No AEs of grade 3 or 4 occurred during the procedures.
DISCUSSION: PHP is a standardised and safe procedure that provides promising response rates and survival data in patients with iCCA, especially in non-metastatic disease.
KEY POINTS: • Percutaneous hepatic perfusion (PHP) offers an additional locoregional therapy strategy for the treatment of unresectable primary or secondary intrahepatic malignancies. • PHP is a standardised and safe procedure that provides promising response rates and survival data in patients with intrahepatic cholangiocarcinoma (iCCA), especially in non-metastatic disease. • Side effects seem to be tolerable and comparable to other systemic or local treatment strategies.

Tamaki M, Nakasone H, Gomyo A, et al.
Lower glomerular filtration rate predicts increased hepatic and mucosal toxicity in myeloma patients treated with high-dose melphalan.
Int J Hematol. 2018; 108(4):423-431 [PubMed] Related Publications
High-dose melphalan followed by autologous hematopoietic stem cell transplantation (ASCT) is a standard treatment for younger myeloma patients. However, the correlation between its toxicity and renal impairment is not clear. We analyzed this relationship, focusing on estimated glomerular filtration rate (eGFR) as an index of renal function. We evaluated 78 multiple myeloma patients who underwent ASCT following high-dose melphalan at our center. Patients were divided into a higher eGFR group (eGFR ≥ 60) and a lower eGFR group (eGFR < 60). Multivariate analyses revealed that lower eGFR was independently associated with alkaline phosphatase elevation (OR 10.2, P = 0.038), mucositis (OR 10.5, P = 0.032), grade 2-4 co-elevation of both aspartate aminotransferase and alanine aminotransferase (OR 21.3, P = 0.016), delay of reticulocyte engraftment (HR 0.524, P = 0.034), and delay of platelet engraftment (HR 0.535, P = 0.0016). However, lower eGFR was not correlated with overall survival or time-to-next treatment. In summary, renal dysfunction secondary to administration of high-dose melphalan was associated with increased hepatic and mucosal toxicity and delay of hematological recovery, but did not affect survival outcomes.

Huis In 't Veld EA, Grünhagen DJ, Deroose JP, et al.
Isolated limb perfusion for unresectable extremity cutaneous squamous cell carcinoma; an effective limb saving strategy.
Br J Cancer. 2018; 119(4):429-434 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A small minority of patients present with locally advanced cutaneous Squamous Cell Carcinoma (cSCC). The aim of this study was to evaluate the effectiveness of Tumour necrosis factor α (TNF) and melphalan based isolated limb perfusion (TM-ILP) as a limb saving strategy for locally advanced extremity cSCC.
METHODS: A retrospective search from prospectively maintained databases, at two tertiary referral centers, was performed to identify patients treated with TM-ILP for locally advanced cSSC of an extremity between 2000 and 2015.
RESULTS: A total of 30 patients treated with TM-ILP for cSCC were identified, with a median age of 71 years (36-92) and 50% female. Response could not be evaluated in 3 patients. After a median follow up of 25 months, the overall response rate was 81% (n = 22), with 16 patients having a complete response (CR, 59%). A total of 7 patients developed local recurrence, with a median time to recurrence of 9 months (Interquartile Range 7-10). Progressive disease was observed in 5 patients (19%). Limb salvage rate was 80%. The overall 2-year survival was 67%.
CONCLUSIONS: TM-ILP should be considered as an option in patients with locally advanced cSCC in specialised centers, resulting in a high limb salvage rate.

Ogura M, Yamamoto K, Morishima Y, et al.
R-High-CHOP/CHASER/LEED with autologous stem cell transplantation in newly diagnosed mantle cell lymphoma: JCOG0406 STUDY.
Cancer Sci. 2018; 109(9):2830-2840 [PubMed] Free Access to Full Article Related Publications
Although induction immunochemotherapy including high-dose cytarabine and rituximab followed by high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) is recommended for younger patients (≤65 years old) with untreated mantle cell lymphoma (MCL), no standard induction and HDC regimen has been established. We conducted a phase II study of induction immunochemotherapy of R-High-CHOP/CHASER followed by HDC of LEED with ASCT in younger patients with untreated advanced MCL. Eligibility criteria included untreated MCL, stage II bulky to IV, and age 20-65 years. Patients received 1 cycle of R-High-CHOP followed by 3 cycles of CHASER every 3 weeks. Peripheral blood stem cells (PBSC) were harvested during CHASER. LEED with ASCT was delivered to patients who responded to R-High-CHOP/CHASER. Primary endpoint was 2-year progression-free survival (PFS). From June 2008 to June 2012, 45 patients (median age 59 years; range 38-65 years) were enrolled. PBSC were successfully harvested from 36 of 43 patients. Thirty-five patients completed ASCT. Two-year PFS was 77% (80% CI 68-84), which met the primary endpoint. Five-year PFS and overall survival were 52% (95% CI 34-68%) and 71% (95% CI 51-84%), respectively. Overall response and complete response rates after induction immunochemotherapy were 96% and 82%, respectively. The most common grade 4 toxicities were hematological. In younger patients with untreated MCL, R-High-CHOP/CHASER/LEED with ASCT showed high efficacy and acceptable toxicity, and it can now be considered a standard treatment option.

Smith HG, Wilkinson MJ, Smith MJF, et al.
The effect of age on outcomes after isolated limb perfusion for advanced extremity malignancies.
Eur J Cancer. 2018; 100:46-54 [PubMed] Related Publications
BACKGROUND: Isolated limb perfusion (ILP) is a well-established treatment for patients with advanced extremity malignancies unsuitable for limb-conserving surgery. However, little is known about the outcomes of this treatment in elderly patients. We sought to determine the effects of age on the tolerability and efficacy of ILP for advanced extremity malignancy.
PATIENTS AND METHODS: Patients undergoing ILP at our institution between January 2005 and January 2018 were identified from a prospectively maintained database. Patients were stratified by pathology (melanoma, soft-tissue sarcoma, other) and age (<75 years and ≥75 years). Outcomes of interest were perioperative morbidity and mortality, locoregional toxicities, response rates and oncological outcomes.
RESULTS: During the study period, a total of 189 perfusions were attempted. Successful perfusions were performed in 179 patients, giving a technical success rate of 94.7%. No difference in perfusion success rates, severe locoregional toxicity and perioperative morbidity or mortality was noted between those aged <75 years and ≥75 years. The overall response rate in melanoma was 82.4%, and no difference in response rates or oncological outcomes between age groups was noted in these patients. The overall response rate in soft-tissue sarcoma was 63.5%, with no difference in response rates noted between age groups. However, patients aged <75 years with soft-tissue sarcoma had prolonged local recurrence-free survival compared with older patients (13 versus 6 months), possibly due to the prevalence of chemosensitive subtypes in the younger age group.
CONCLUSION: ILP is an effective treatment for advanced extremity malignancies in the elderly, with comparable response rates and toxicities to younger patients.

Nguyen VP, Landau H, Quillen K, et al.
Modified High-Dose Melphalan and Autologous Stem Cell Transplantation for Immunoglobulin Light Chain Amyloidosis.
Biol Blood Marrow Transplant. 2018; 24(9):1823-1827 [PubMed] Related Publications
High-dose melphalan and autologous stem cell transplantation (HDM/SCT) have been used in patients with immunoglobulin light chain (AL) amyloidosis for over 2 decades now with durable responses, prolonged survival, and decreasing treatment-related mortality. Historically, patients with poorer baseline functional status, advanced age, renal compromise, and cardiac involvement have been treated with a risk-adapted modified conditioning dose of melphalan (mHDM) of 100 to 140 mg/m

Sidiqi MH, Aljama MA, Muchtar E, et al.
Autologous Stem Cell Transplant for Immunoglobulin Light Chain Amyloidosis Patients Aged 70 to 75.
Biol Blood Marrow Transplant. 2018; 24(10):2157-2159 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Autologous stem cell transplantation (ASCT) has been used in treatment for immunoglobulin light chain (AL) amyloidosis for over 2 decades and is generally reserved for patients younger than 70 years. Herein we report on outcomes of ASCT in a cohort of patients with AL amyloidosis aged 70 years or older. Between August of 2002 and April of 2017, 34 patients aged 70 years or older, with biopsy-proven AL amyloidosis, received an ASCT at the Mayo Clinic Rochester. Seventy percent of patients (n = 24) were transplanted within 6 months of diagnosis, and 74% (n = 25) received reduced-intensity conditioning with melphalan <200 mg/m

Boone BA, Perkins S, Bandi R, et al.
Hepatic artery infusion of melphalan in patients with liver metastases from ocular melanoma.
J Surg Oncol. 2018; 117(5):940-946 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND AND OBJECTIVES: Ocular melanoma has a predilection for liver metastases. Systemic treatment is ineffective and the optimal regional therapy approach is poorly defined. Isolated hepatic perfusion (IHP) with melphalan has emerged as a viable treatment option, however a subset of patients are not candidates for this treatment. We therefore sought to determine if melphalan could be safely administered via the hepatic artery for these patients.
METHODS: A retrospective review of patients treated with hepatic artery infusion (HAI) of melphalan was undertaken. All patients had contraindications to IHP and were without other therapy options. Melphalan infusion was repeated every four weeks with consideration for dose escalation in the absence of toxicity or significant disease progression.
RESULTS: Fourteen patients were treated with HAI of melphalan from 2010 to 2015. All patients had hepatic dysfunction or prohibitive tumor volume precluding IHP. There were no procedure-related complications. Three patients (21%) died within 30 days and the median survival was 2.9 months. Elevated baseline bilirubin > 2.5 mg/dL was associated with worse overall survival (0.93 vs 6.3 months, P < 0.05).
CONCLUSION: HAI of melphalan is safe and feasible for patients with metastatic ocular melanoma. Further study to determine the optimal utilization of this treatment approach is warranted.

Al Malki MM, Nathwani N, Yang D, et al.
Melphalan-Based Reduced-Intensity Conditioning is Associated with Favorable Disease Control and Acceptable Toxicities in Patients Older Than 70 with Hematologic Malignancies Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.
Biol Blood Marrow Transplant. 2018; 24(9):1828-1835 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Allogeneic hematopoietic stem cell transplantation (alloHCT) is offered increasingly to elderly patients with hematologic malignancies. However, outcome data in those who are 70 years or older are limited, and no standard conditioning regimen has been established for this population. In this retrospective study we evaluated the outcome of 53 consecutive patients aged 70 years and older who underwent alloHCT with melphalan-based reduced-intensity conditioning (RIC) at City of Hope. Engraftment was prompt, with median time to neutrophil engraftment of 15 days. More than 95% of patients achieved complete donor chimerism within 6 weeks from HCT, consistent with the "semiablative" nature of this regimen. With a median follow-up of 31.1 months, the 2-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) were 68.9%, 63.8%, and 17.0%, respectively. Cumulative incidence of relapse at 1 and 2 years was 17.0% and 19.3%, respectively. One hundred-day cumulative incidence of grades II to IV acute graft-versus-host disease was 37.7% (grades III to IV, 18.9%), and 2-year cumulative incidence of chronic graft-versus-host disease was 61.9% (extensive, 45.9%). The only significant predictor for poor OS was high/very high disease risk index. Transplant-related complications and morbidities observed here did not differ from the commonly expected in younger patients treated with RIC. In conclusion, alloHCT with a melphalan-based conditioning regimen is associated with acceptable toxicities and NRM, lower incidence of relapse, and favorable OS and PFS in patients aged 70 years or older.

Dhakal B, D'Souza A, Lakshman A, et al.
Pharmacokinetics of High-Dose Propylene Glycol-Free Melphalan in Multiple Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplantation.
Biol Blood Marrow Transplant. 2018; 24(8):1610-1614 [PubMed] Related Publications
High-dose melphalan followed by autologous stem cell transplant (ASCT) is standard of care for eligible patients with multiple myeloma (MM). Evomela (propylene glycol-free melphalan HCl [PG-Free Mel]; Spectrum Pharmaceuticals, Irvine, CA) was approved by the US Food and Drug Administration as conditioning therapy for ASCT in MM in 2 daily 100-mg/m

Fan FS, Yang CF
Complete response to orally administered melphalan in malignant pleural effusion from an occult female genital organ primary neoplasm with BRCA1/2 mutations: a case report.
J Med Case Rep. 2018; 12(1):122 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Definite diagnosis of metastasis from unknown primary depends on a comprehensive immunohistochemical investigation of tumor specimen. Accurate identification of the origin site usually helps a lot in choosing the most appropriate treatment. Molecular characterization provides more chance of a cure. Echoing modern medical development, BRCA1/2 mutations have been correlated with high efficiency of poly(adenosine diphosphate-ribose) polymerase inhibitors in ovarian cancer. While a previous case report demonstrated a surprising cure of platinum-resistant ovarian cancer with BRCA2 mutation by orally administered melphalan.
CASE PRESENTATION: A 53-year-old Taiwanese woman's malignant pleural effusion was diagnosed to be a metastasis from an occult cancer in female genital organ by diligent pathological study despite absence of image evidence. She resolutely refused intravenously administered chemotherapy. After failure of anti-estrogen tamoxifen, orally administered melphalan achieved excellent complete remission. Pathogenic homozygous BRCA1 and BRCA2 mutations were later detected in tumor cells by next-generation sequencing. The same BRCA2 mutation exists in a heterozygous status in the germline deoxyribonucleic acid.
CONCLUSIONS: This is so far the second report of long-term remission of advanced female genital organ cancer with BRCA mutations achieved by orally administered melphalan. BRCA1/2 mutations and even all "BRCAness" of malignancy, at least ovarian cancer and ovarian-related cancers, probably not only correlate with high efficacy of poly(adenosine diphosphate-ribose) polymerase inhibitors but also lead to a high-potential cure by orally administered melphalan. We recommend that clinical trials that test this assumption be carefully designed and sophisticatedly performed.

Hathi DK, DeLassus EN, Achilefu S, et al.
Imaging Melphalan Therapy Response in Preclinical Extramedullary Multiple Myeloma with
J Nucl Med. 2018; 59(10):1551-1557 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Multiple myeloma (MM) is a debilitating neoplasm of terminally differentiated plasma B cells that resulted in over 13,000 deaths in 2017 alone. Combination therapies involving melphalan, a small-molecule DNA alkylating agent, are commonly prescribed to patients with relapsed or refractory MM, necessitating the stratification of responding patients to minimize toxicities and improve quality of life. Here, we evaluated the use of 3,4-dihydroxy-6-

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