"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)
Latest Research Publications
Web Resources: Melphalan (6 links)
This list of publications is regularly updated (Source: PubMed).
Outcomes with two different schedules of bortezomib, melphalan, and prednisone (VMP) for previously untreated multiple myeloma: matched pair analysis using long-term follow-up data from the phase 3 VISTA and PETHEMA/GEM05 trials.
Ann Hematol. 2016; 95(12):2033-2041 [PubMed] Related Publications
TRIAL REGISTRATIONS: NCT00111319, NCT00443235.
Superselective intra-arterial chemotherapy in the primary management of advanced intra-ocular retinoblastoma: first 4-year experience from a single institution in Turkey.
Acta Ophthalmol. 2016; 94(7):e644-e651 [PubMed] Related Publications
METHODS: From October 2011 to September 2015, 26 group D eyes of 24 treatment-naïve retinoblastoma patients managed primarily with IAC were evaluated in this prospective study.
RESULTS: Of 76 procedures, ophthalmic artery cannulation failed in two patients with unilateral involvement. In the remaining 22 patients (24 eyes), the mean age at diagnosis was 18 months (range, 6-55 months). Each eye received a mean of 3 IAC sessions/eye (range, 2-5 sessions). After a median follow-up of 29 months (range, 6-55 months), complete regression of the main tumour was achieved in 23 of 24 eyes. One eye with partial regression required enucleation due to ciliary body involvement by the tumour. Overall, 16 eyes (66.6%) were salvaged with primary IAC with or without additional local treatments, and eight (33.3%) required enucleation. The main IAC-related periocular complications included transient eyelid oedema (n = 13), ptosis (n = 6) and forehead hyperpigmentation (n = 3), each resolving in 2 weeks to 4 months. Intra-ocular complications included chorioretinal atrophy (n = 9), newly noted retinal detachment (n = 5) and vitreous haemorrhage (n = 1). Kaplan-Meier eye estimates of enucleation-free survival rates were 83.3% (95% CI, 68.4-98.1%), 69.1% (95% CI, 49.8-88.3%) and 62.9 (95% CI, 41.9-83.8%) at 6 months, 1 and 2 years, respectively, and stable thereafter.
CONCLUSION: Our first 4-year experience in Turkey showed that enucleation or external-beam radiotherapy could be avoided in two-thirds of eyes with advanced intra-ocular retinoblastoma managed primarily with IAC.
The role of high-dose melphalan and autologous stem cell transplant in the rapidly evolving era of modern multiple myeloma therapy.
Clin Adv Hematol Oncol. 2016; 14(9):719-28 [PubMed] Related Publications
Retinoblastoma Control With Primary Intra-arterial Chemotherapy: Outcomes Before and During the Intravitreal Chemotherapy Era.
J Pediatr Ophthalmol Strabismus. 2016; 53(5):275-84 [PubMed] Related Publications
METHODS: In this retrospective interventional case series at a tertiary referral center, 66 eyes of 66 patients with untreated unilateral retinoblastoma were used. intraarterial chemotherapy into the ophthalmic artery under fluoroscopic guidance was performed using melphalan in every case, with additional topotecan as necessary. Intravitreal chemotherapy using melphalan and/or topotecan was employed as needed for active vitreous seeding. Globe salvage was measured based on the International Classification of Retinoblastoma (ICRB) during two eras.
RESULTS: The two eras encompassed 2008 to 2012 (intraarterial chemotherapy alone, Era I) and 2012 to 2015 (intraarterial chemotherapy plus intravitreal chemotherapy, Era II). Over this period, there were 66 patients with unilateral untreated retinoblastoma treated with primary intra-arterial chemotherapy. A comparison of features (Era I vs Era II) revealed no significant difference in mean patient age (24 vs 24 months), ICRB groups, mean largest tumor diameter (19 vs 17 mm), mean largest tumor thickness (10 vs 10 mm), vitreous seed presence (56% vs 59%), subretinal seed presence (67% vs 62%), retinal detachment (70% vs 66%), or vitreous hemorrhage (0% vs 5%). There was no significant difference in mean number of intra-arterial chemotherapy cycles (3 vs 3.1) or intraarterial chemotherapy dosages. Following therapy, there was a significant difference (Era I vs Era II) in the need for enucleation overall (44% vs 15%, P = .012), especially for group E eyes (75% vs 27%, P = .039). Four of the eyes that initiated therapy in Era I later required intravitreal chemotherapy during Era II. The enucleation rate was 0% for groups B and C in both eras and non-significant for group D (23% vs 13%). There were no patients with stroke, seizure, limb ischemia, extraocular tumor extension, secondary leukemia, metastasis, or death.
CONCLUSIONS: The current era of retinoblastoma management using intra-arterial chemotherapy plus additional intravitreal chemotherapy (as needed for vitreous seeding) has improved globe salvage in eyes with advanced retinoblastoma. [J Pediatr Ophthalmol Strabismus. 2016;53(5):275-284.].
Multiple Differential Networks Strategy Reveals Carboplatin and Melphalan-Induced Dynamic Module Changes in Retinoblastoma.
Med Sci Monit. 2016; 22:1508-15 [PubMed] Free Access to Full Article Related Publications
In vitro and in vivo activity of melflufen (J1)in lymphoma.
BMC Cancer. 2016; 16:263 [PubMed] Free Access to Full Article Related Publications
METHODS: Cytotoxicity of melflufen was assayed in lymphoma cell lines and in primary tumor cells with the Fluorometric Microculture Cytotoxicity Assay and cell cycle analyses was performed in two of the cell lines. Melflufen was also investigated in a xenograft model with subcutaneous lymphoma cells inoculated in mice.
RESULTS: Melflufen showed activity with cytotoxic IC50-values in the submicromolar range (0.011-0.92 μM) in the cell lines, corresponding to a mean of 49-fold superiority (p < 0.001) in potency vs. melphalan. In the primary cultures melflufen yielded slightly lower IC50-values (2.7 nM to 0.55 μM) and an increased ratio vs. melphalan (range 13-455, average 108, p < 0.001). Treated cell lines exhibited a clear accumulation in the G2/M-phase of the cell cycle. Melflufen also showed significant activity and no, or minimal side effects in the xenografted animals.
CONCLUSION: This study confirms previous reports of a targeting related potency superiority of melflufen compared to that of melphalan. Melflufen was active in cell lines and primary cultures of lymphoma cells, as well as in a xenograft model in mice and appears to be a candidate for further evaluation in the treatment of this group of malignant diseases.
Diffuse chorioretinal atrophy after a single standard low- dose intravitreal melphalan injection in a child with retinoblastoma: a case report.
BMC Ophthalmol. 2016; 16:27 [PubMed] Free Access to Full Article Related Publications
CASE PRESENTATION: A 12-month-old female child without a family history of retinoblastoma presented with unilateral group C retinoblastoma in her right eye. A solitary tumour with retinal breaks on the tumour surface, and vitreous seeds overlying the tumour were observed at the 8 o'clock position of the retina. After two cycles of intra-arterial chemotherapy with melphalan, the main tumour displayed significant regression, but the vitreous seeds overlying the main tumour were still active. Because of the persistence of vitreous seeds and the inadequate response to intra-arterial melphalan treatment, intravitreal melphalan (8 μg in 0.05 mL) was injected using a 32-gauge needle 2.5 mm from the 5 o'clock position of the limbus, the meridian opposite to the vitreous seeds. After 1 month, the retina around the injection site demonstrated diffuse retinal pigment epithelium alterations with dense hard exudates. Although the main retinal mass, and vitreous seeds resolved, the hard exudates persisted for more than 2 years after the single low-dose melphalan injection.
CONCLUSIONS: Intravitreal melphalan injections should be cautiously used for eyes with refractory seeds, particularly when multiple injections are required to control retinoblastoma seeds. Dose- related retinal toxicity could occur in pre-treated eyes even when a relatively low standard dose is used. Such patients should be followed up closely to monitor the treatment response and to assess potential delayed toxicity.
Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma.
Blood. 2016; 127(9):1109-16 [PubMed] Related Publications
Phagocyte function decreases after high-dose treatment with melphalan and autologous stem cell transplantation in patients with multiple myeloma.
Exp Hematol. 2016; 44(5):342-351.e5 [PubMed] Related Publications
LACE versus BEAM conditioning in relapsed and refractory lymphoma transplant: retrospective multicenter analysis of toxicity and efficacy.
Int J Hematol. 2016; 103(3):292-8 [PubMed] Related Publications
Inhibiting the anaphase promoting complex/cyclosome induces a metaphase arrest and cell death in multiple myeloma cells.
Oncotarget. 2016; 7(4):4062-76 [PubMed] Free Access to Full Article Related Publications
Ocular dysmotility after intra-arterial chemotherapy for retinoblastoma.
J AAPOS. 2015; 19(6):574-7 [PubMed] Related Publications
Bone marrow PMN-MDSCs and neutrophils are functionally similar in protection of multiple myeloma from chemotherapy.
Cancer Lett. 2016; 371(1):117-24 [PubMed] Free Access to Full Article Related Publications
Comparison of toxicity following different conditioning regimens (busulfan/melphalan and carboplatin/etoposide/melphalan) for advanced stage neuroblastoma: Experience of two transplant centers.
Pediatr Transplant. 2016; 20(2):284-9 [PubMed] Related Publications
Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplantation Cyclophosphamide in Children with Advanced Acute Leukemia with Fludarabine-, Busulfan-, and Melphalan-Based Conditioning.
Biol Blood Marrow Transplant. 2016; 22(3):499-504 [PubMed] Related Publications
Selective Ophthalmic Artery Infusion Chemotherapy for Advanced Intraocular Retinoblastoma: CCHMC Early Experience.
J Pediatr Hematol Oncol. 2016; 38(1):65-9 [PubMed] Related Publications
First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies.
Invest New Drugs. 2015; 33(6):1232-41 [PubMed] Related Publications
METHODS: This was a prospective, single-armed, open-label, first-in-human, dose-finding phase I/IIa study in 45 adult patients with advanced and progressive solid tumors without standard treatment options. Most common tumor types were ovarian carcinoma (n = 20) and non-small-cell lung cancer (NSCLC, n = 11).
RESULTS: In the dose-escalating phase I part of the study, seven patients were treated with increasing fixed doses of melflufen (25-130 mg) Q3W. In the subsequent phase IIa part, 38 patients received in total 115 cycles of therapy at doses of 30-75 mg. No dose-limiting toxicities (DLTs) were observed at 25 and 50 mg; at higher doses DLTs were reversible neutropenias and thrombocytopenias, particularly evident in heavily pretreated patients, and the recommended phase II dose (RPTD) was set to 50 mg. Response Evaluation Criteria In Solid Tumors (RECIST) evaluation after 3 cycles of therapy (27 patients) showed partial response in one (ovarian cancer), and stable disease in 18 patients. One NSCLC patient received nine cycles of melflufen and progressed after 7 months of therapy.
CONCLUSIONS: In conclusion, melflufen can safely be given to cancer patients, and the toxicity profile was as expected for alkylating agents; RPTD is 50 mg Q3W. Reversible and manageable bone marrow suppression was identified as a DLT. Clinical activity is suggested in ovarian cancer, but modest activity in treatment of refractory NSCLC.
A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells.
Clin Cancer Res. 2016; 22(5):1222-33 [PubMed] Free Access to Full Article Related Publications
EXPERIMENTAL DESIGN: Here we studied the potential utility of miR-221/222 inhibition in sensitizing refractory multiple myeloma cells to melphalan.
RESULTS: miR-221/222 expression inversely correlated with melphalan sensitivity of multiple myeloma cells. Inhibition of miR-221/222 overcame melphalan resistance and triggered apoptosis of multiple myeloma cells in vitro, in the presence or absence of human bone marrow (BM) stromal cells. Decreased multiple myeloma cell growth induced by inhibition of miR-221/222 plus melphalan was associated with a marked upregulation of pro-apoptotic BBC3/PUMA protein, a miR-221/222 target, as well as with modulation of drug influx-efflux transporters SLC7A5/LAT1 and the ABC transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory multiple myeloma xenografts with systemic locked nucleic acid (LNA) inhibitors of miR-221 (LNA-i-miR-221) plus melphalan overcame drug resistance, evidenced by growth inhibition with significant antitumor effects together with modulation of PUMA and ABCC1 in tumors retrieved from treated mice.
CONCLUSIONS: Taken together, our findings provide the proof of concept that LNA-i-miR-221 can reverse melphalan resistance in preclinical models of multiple myeloma, providing the framework for clinical trials to overcome drug resistance, and improve patient outcome in multiple myeloma.
Cost-effectiveness of lenalidomide plus dexamethasone vs. bortezomib plus melphalan and prednisone in transplant-ineligible U.S. patients with newly-diagnosed multiple myeloma.
J Med Econ. 2016; 19(3):243-58 [PubMed] Related Publications
METHODS: A partitioned survival model was developed to estimate expected life-years (LYs), quality-adjusted LYs (QALYs), direct costs and incremental costs per QALY and LY gained associated with use of Rd vs VMP over a patient's lifetime. Information on the efficacy and safety of Rd and VMP was based on data from multinational phase III clinical trials and a network meta-analysis. Pre-progression direct costs included the costs of Rd and VMP, treatment of adverse events (including prophylaxis) and routine care and monitoring associated with MM. Post-progression direct costs included costs of subsequent treatment(s) and routine care and monitoring for progressive disease, all obtained from published literature and estimated from a U.S. payer perspective. Utilities were obtained from the aforementioned trials. Costs and outcomes were discounted at 3% annually.
RESULTS: Relative to VMP, use of Rd was expected to result in an additional 2.22 LYs and 1.47 QALYs (discounted). Patients initiated with Rd were expected to incur an additional $78,977 in mean lifetime direct costs (discounted) vs those initiated with VMP. The incremental costs per QALY and per LY gained with Rd vs VMP were $53,826 and $35,552, respectively. In sensitivity analyses, results were found to be most sensitive to differences in survival associated with Rd vs VMP, the cost of lenalidomide and the discount rate applied to effectiveness outcomes.
CONCLUSIONS: Rd was expected to result in greater LYs and QALYs compared with VMP, with similar overall costs per LY for each regimen. Results of this analysis indicated that Rd may be a cost-effective alternative to VMP as initial treatment for transplant-ineligible patients with MM, with an incremental cost-effectiveness ratio well within the levels for recent advancements in oncology.
Combined intravitreal melphalan and intravenous/intra-arterial chemotherapy for retinoblastoma with vitreous seeds.
Graefes Arch Clin Exp Ophthalmol. 2016; 254(2):391-4 [PubMed] Related Publications
METHODS: In this retrospective case series, eight eyes from eight retinoblastoma patients with vitreous seeds were included. All eyes received 20-30 μg of intravitreal melphalan accompanied by intravenous and intra-arterial chemotherapy. Triple freeze-thaw cryotherapy was performed when withdrawing the needle from the eye to prevent tumor dissemination.
RESULTS: Tumors and vitreous seeds regressed in all eyes. The mean number of intravitreal melphalan injections was 3.25 (median 3.50, range 2-4). Globe salvage was attained in seven of eight eyes (87.5 %). Enucleation was performed in one case, in which the pathologic section showed no residual tumor and tumor-free resection margins. Serous retinal detachment was observed in four eyes (50 %), and vitreous hemorrhage developed in two (25 %). Retinal pigment epithelium atrophy or mottling was found in three eyes (37.5 %). There were no cases of extraocular tumor extension or remote metastasis.
CONCLUSIONS: Combined intravitreal melphalan and intravenous/intra-arterial chemotherapy was effective for tumor and vitreous seeding control, but vision-threatening complications such as vitreous hemorrhage or serous retinal detachment occurred in half the cases.
Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM.
Blood. 2016; 127(4):420-5 [PubMed] Related Publications
Outcomes of Haploidentical Stem Cell Transplantation for Lymphoma with Melphalan-Based Conditioning.
Biol Blood Marrow Transplant. 2016; 22(3):493-8 [PubMed] Related Publications
Intravitreal Lower-Dose (20 µg) Melphalan for Persistent or Recurrent Retinoblastoma Vitreous Seeds.
Ophthalmic Surg Lasers Imaging Retina. 2015; 46(9):942-8 [PubMed] Related Publications
PATIENTS AND METHODS: Retrospective review of all patients with active VS treated with lower-dose intravitreal melphalan (20 µg/0.1 mL) on a monthly basis until complete VS regression was achieved.
RESULTS: A total of 14 injections were delivered to seven eyes of seven patients (range: 1-4; median: 2). At a median follow-up of 20 months (range: 12-32 months), complete regression of VS was achieved in all cases (100%), and globe salvage was achieved in six cases (86%). One eye required enucleation for solid tumor recurrence. Side effects of retinal pigment epithelium mottling at the site of injection was noted in two eyes (29%).
CONCLUSION: The 2-year results of this study suggest that standard lower-dose (20 µg) intravitreal melphalan is safe and highly effective for the management of viable VS from retinoblastoma.
Synergistic cytotoxicity against human tumor cell lines by oncolytic adenovirus dl1520 (ONYX-015) and melphalan.
Tumori. 2016 Jan-Feb; 102(1):31-9 [PubMed] Related Publications
METHODS: As a model system in which to test this potential, representative cell lines from 2 common cancer types, oral squamous cell carcinoma (HN-5a) and colon adenocarcinoma (HT-29), were chosen, as well as platinum-drug-resistant variants of each.
RESULTS: Following preliminary screening of virus and drug combinations, dl1520 and melphalan were found to synergistically inhibit proliferation of all the cancer cell lines. Melphalan pretreatment or cotreatment with dl1520 enhanced inhibition of proliferation by dl1520 by up to 60% and increased apoptosis by up to 25%. The tight-junction protein CAR (coxsackie and adenovirus receptor), via which adenovirus enters cells, was not upregulated by treatment with melphalan, suggesting that other mechanisms contribute to synergy.
CONCLUSIONS: The synergy between melphalan and dl1520 suggests that tumor-selective cell killing by oncolytic viruses may be augmented by combining with cytotoxic drugs.
Intraocular surgery with melphalan irrigation for vitreous hemorrhage in an only eye with retinoblastoma.
Eur J Ophthalmol. 2015; 26(1):e17-9 [PubMed] Related Publications
METHODS: Vitreous hemorrhage occurred in the only eye of a 4-year-old boy after treatment for recurrent multifocal group C retinoblastoma with systemic chemotherapy (carboplatin, etoposide, and cyclophosphamide; and vincristine, cyclophosphamide, and doxorubicin), ruthenium brachytherapy with plaque repositioning, cryotherapy, and external radiotherapy. The VH developed 8 months after repeated brachytherapy with subsequent intravitreal melphalan chemotherapy. The patient's parents refused to remove the eye. The fellow eye was enucleated earlier because of VH and secondary glaucoma, without histologic signs of a viable tumor. Pars plana lensectomy, 25-G vitrectomy with melphalan irrigation (5 μg/mL), and silicone oil tamponade were performed.
RESULTS: No ophthalmoscopic or morphologic signs of a viable tumor were detected. Four months later, the silicone oil was removed. Visual acuity was 20/200 with aphakic correction. Follow-up for 34 months revealed no signs of tumor recurrence or dissemination.
CONCLUSIONS: Despite the high risk of intraocular surgery, the need to preserve the only potentially seeing eye with treated retinoblastoma may require PPV. Thus, in unclear cases of VH with suspected viable tumor, PPV with intraocular melphalan irrigation, with caution, may be a reasonable procedure.
A case of melphalan sustained accumulation in an 80-year old patient.
Int J Clin Pharm. 2015; 37(6):984-7 [PubMed] Related Publications
Anterior Ocular Toxicity of Intravitreous Melphalan for Retinoblastoma.
JAMA Ophthalmol. 2015; 133(12):1459-63 [PubMed] Free Access to Full Article Related Publications
OBSERVATIONS: Our clinic cohort included 76 patients who received intravitreous injections of melphalan at Memorial Sloan Kettering Cancer Center from September 12, 2012, through April 15, 2015; data analysis was performed from April 15 through May 15, 2015. We report a series of 5 patients from this cohort who developed anterior segment toxic effects. These abnormalities were found at the injection site or within the meridian of the injection and included a traumatic cataract following an injection at an outside hospital, iris depigmentation and thinning, iris recession with retinal necrosis and hypotony, a filtering conjunctival bleb, and focal scleromalacia with localized pigmentation.
CONCLUSIONS AND RELEVANCE: Intravitreous injection of melphalan may result in toxic effects on the anterior segment of the eye, in addition to retinal abnormalities, and appears to be more common in the meridian of the injection where the drug concentration is highest.
Fertility After Treatment With High Dose Melphalan in Women With Acute Myelogenous Leukemia.
Pediatr Blood Cancer. 2016; 63(2):334-6 [PubMed] Related Publications
PROCEDURE: The fertility assessment included a questionnaire, blood tests for luteinizing hormone, follicle stimulating hormone and anti mullerian hormone (AMH), and a gynecological ultrasound exam for antral follicular count (AFC).
RESULTS: Eight female survivors participated. Although fertility assessment showed considerable damage to ovarian reserve in all participants, four of the eight female survivors conceived and bore children without medical intervention.
CONCLUSION: In this cohort, HDM treatment reduced fertility potential but did not preclude fecundity. Early referral to a fertility clinic and long term follow-up including serial measurements of AMH levels and AFC for female patients receiving HDM are recommended.
Intra-Arterial Chemotherapy for Retinoblastoma: A Single-Center Experience.
Ophthalmologica. 2015; 234(4):227-32 [PubMed] Related Publications
MATERIALS AND METHODS: This was a retrospective study of patients with intraocular retinoblastoma who were treated with IACT from December 2011 to May 2014. A total of 56 eyes of 46 consecutive patients (30 males and 16 females) were included in the study. Forty-four eyes received systemic chemotherapy upon diagnosis (systemic chemotherapy group, SCG), and 12 eyes were those of newly diagnosed patients (primary intra-arterial melphalan group, PIAG). The choice of the IACT dose was based on age. Tumor control and globe salvage with IACT were analyzed. Complete blood counts were examined 7 days after the IACT for systemic toxicity. Ocular toxicities such as proptosis, eyelid edema, ocular motility, and retinal and optic atrophy were assessed by an ocular oncologist with regular ophthalmologic examinations.
RESULTS: Enucleation was avoided overall in 66% (37/56) of the eyes, including 75% (9/12) in the PIAG and 64% (28/44) in the SCG patients. The 1-year enucleation-free survival rate was 56.7% at a median follow-up time of 11.9 months (range 0.27-27.6). IACT was administered in a total of 124 cycles (ranging from 1 to 7 cycles, mean 2.3). The responses were as follows: regression of the retinal tumor in 27 eyes and improvements in vitreous seeding in 5 of 15 eyes. The further treatment requirements after IACT were as follows: enucleation in 19 eyes (10 with vitreous seeding), radiotherapy in 3 eyes, systemic chemotherapy in 1 eye, and local therapy in 1 eye. No severe systemic side effects occurred. Transient swelling of the eyelids (22 patients), conjunctival chemosis (12 patients), upper eyelid ptosis (5 patients), redness over the frontal area (3 patients), limitation of ocular motility (3 patients) and mild proptosis (1 patient) were detected. Retinal pigment epithelial alterations (30 patients) and optic atrophy (3 patients) were seen in the late follow-up.
CONCLUSIONS: Globe salvage and avoidance of radiotherapy may be achieved by IACT with limited toxicity. This treatment is efficient, repeatable and safe.