Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: ADIENNE S.r.l. S.U., Via Galileo Galilei, 19, 20867 Caponago (MB), Italy, tel: +39 0240700445, e-mail: adienne@adienne.com
Pharmacotherapeutic group: antineoplastic and immunomodulating agents, antineoplastic agents, alkylating agents, nitrogen mustard analogues
ATC code: L01AA03
Melphalan is a bifunctional alkylating agent that prevents the separation and replication of DNA. Formation of carbonium intermediates from each of the two bis-2-chloroethyl groups enables alkylation through covalent binding with the 7-nitrogen of guanine on DNA, cross-linking the two DNA strands and thereby preventing cell replication.
Documentation on the safety and efficacy of PHELINUN in combination with other cytotoxic medicinal products derives from literature review. In total the studies report efficacy results for 3,096 patients of whom 607 were from studies reporting results only in the paediatric population (under the age of 18 years). Endpoints in these studies were overall survival (OS), disease-free survival (DFS), event-free survival (EFS) and non-relapse mortality (NRM).The results of published clinical studies supporting the efficacy of melphalan are summarised below divided between adult and pediatric population.
Baron et al., 2015
This retrospective study, performed by the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation, compared the outcomes for a cohort of 394 AML patients receiving a sibling HSCT after fludarabine-busulfan (n=218) or fludarabine-melphalan (n=176). Busulfan dose was ranging from 7.1 to 8.9 mg/kg [oral] or from 6.0 to 6.9 mg/kg [intravenous]; melphalan dose was ranged between 130 to 150 mg/m². Both are considered RIC.
There was a statistically significant reduction in relapse risk at 2 years for fludarabine-melphalan (FM) versus fludarabine-busulfan (FB) in AML patients (FM 20%, FB 30%; p=0.007) which was confirmed in multivariate analysis (HR 0.5, 95%CI 0.3-0.8, p=0.01).
Kawamura et al., 2017
This retrospective study performed in Japan compared the transplant outcomes of patients aged 50 years or older with AML, ALL or MDS after fludarabine with melphalan (140 mg/m² i.v.) (FM, n=423), fludarabine with intermediate doses of busulfan (6.4 mg/kg i.v.) (FB2, n=463) and fludarabine with higher doses of busulfan (12.8 mg/kg i.v.) (FB4, n=721). FM and FB2 are considered RIC-regimens and FB4 is considered a MAC regimen. There was a statistically significant reduction in relapse risk at 3 years for fludarabine-melphalan versus fludarabine-busulfan intermediate dose (FB2) in AML/ALL/MDS patients (FM 27.4%, FB2 37.2%; p=0.0027), confirmed in multivariate analysis (HR 0.56, 95% CI 0.42-0.74, p<0.001).
Eom et al., 2013
This case-control study performed in South Korea in high-risk ALL patients in first or second complete remission, compared outcomes after RIC (melphalan 140 mg/m² and fludarabine 150 mg/m²; n=60) or MAC (TBI 13,2 Gy + cyclophosphamide 120 mg/kg; n=120) allo-HSCT. OS rate at 5 years for fludarabine-melphalan was 54.5%. There was no statistically significant difference in OS-rate at 5 years for fludarabine-melphalan versus TBI-cyclophosphamide in high-risk ALL patients, despite RIC-patients being older or having more co-morbidities and therefore ineligible for myeloablative conditioning.
Three retrospective studies demonstrated the safety and efficacy of PHELINUN in combination with other cytotoxic medicinal products prior to allogeneic HPCT in the paediatric population with malignant haematological diseases including AML and MDS.
Lucchini et al. 2017
This retrospective study, performed by the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation, compared the outcomes for children >2 to <18 years of age undergoing a first allogeneic HSCT from a matched sibling or unrelated donor for AML in CR1 after either Busulfan-Cyclophosphamide-Melphalan (140 mg/m²) (n=133), Busulfan-Cyclophosphamide (n=389) or TBI-cyclophosphamide (n=109). All are considered MAC. There was a statistically significant reduction in relapse rate at 5 years for busulfancyclophosphamide-melphalan (BuCyMel) versus TBI-cyclophosphamide (TBICy) and busulfan-cyclophosphamide (BuCy): (BuCyMel 14.7%, TBICy 30%, BuCy 31.5%; p<0.01) confirmed in multivariate analysis (OR 0.44, 95% CI 0.25-0.80; p<0.01). OS-rate and NRM-rate at 5 years for the BuCyMel regimen were 76.6% and 10.8%, with no statistically significant differences between groups in OS or NRM-rate at 5 years in multivariate analysis.
Locatelli et al., 2015
This retrospective study, performed by the AIEOP group analysed the results of 143 children including 39 patients between 0-1 years of age and 17 between 1-2 years who were given an allo-HSCT for consolidating remission after achievement of CR1 in AML. The conditioning regimen was busulfan, cyclophosphamide and melphalan (140 mg/m²).
In a subgroup analysis of different age categories (<1 year, 1-2 year, 2-10 year, >10 year) there was no statistically significant difference in disease-free survival at 8 years. Analysis of the association of age and the endpoints OS and TRM was not reported.
Strahm et al., 2011
This retrospective study, performed by the European Working Group of MDS in Childhood, analysed 97 children with MDS treated with an allo-HSCT following induction by BuCyMel (melphalan 140 mg/m² single dose). OS-rate was 63%, EFS-rate was 59% and relapse rate was 21% at 5 years.
The study by Lucchini et al., 2017, did not include children below the age of two, and the study by Locatelli et al., 2015, did not report OS, safety data and TRM separately for this age category. Furthermore, in the study by Sauer et al., 2019, assessing the BuCyMel regimen in children with AML, TRM correlated with age with a rate of 9% in children younger than 12 years and 31% in older children and adolescents. Therefore, safety and efficacy in children <2 years of age with AML have not been established and melphalan should not be used in children with AML >12 years of age (see section 4.4).
Ten studies assessed the safety and efficacy of PHELINUN in combination with other cytotoxic medicinal products prior to allogeneic HSCT in a total of 504 patients including the paediatric population (age range 2 months – 18 years) with non malignant haematological diseases including thalassaemia, sickle-cell disease, hemophagocytic lymphohistiocytosis (HLH) and X-linked lymphoproliferative disease, combined immune deficiency and common variable immunodeficiency, severe combined immune deficiency (SCID), non-Fanconi anaemia marrow failure disorders and metabolic disorders. Most studies used a RIC-regimen of alemtuzumab, fludarabine and melphalan 140 mg/m². The largest study was performed by Marsh et al. 2015.
Marsh et al. 2015
In this restrospective study on allo-HSCT in non-malignant haematological diseases, 210 children received a RIC regimen of alemtuzumab, fludarabine, and melphalan 140 mg/m². The OS reported at 1 year was 78% and at 3 years was 69%. Three-year EFS was 84% for patients who underwent transplantation with an HLA-matched related donor compared with 64%, 57% and 14% for patients who underwent transplantation with a matched unrelated donor, 1 allele mismatched donor, or 2 allele mismatched donor, respectively (P < .001). Five % of patients required retransplantation due to graft loss.
The absorption of oral melphalan is highly variable with respect to both the time to first appearance of the medicinal product in plasma and peak plasma concentration. In studies of the absolute bioavailability of melphalan, the mean absolute bioavailability ranged from 56 to 85%.
Intravenous administration can be used to avoid variability in absorption associated with myeloablative treatment.
Melphalan is distributed in most tissues of the body. It is moderately bound to plasma proteins with reported binding ranging from 69% to 78%. There is evidence that the protein binding is linear in the range of plasma concentrations usually achieved in standard dose therapy, but that the binding may become concentration-dependent at the concentrations observed in high-dose therapy. Serum albumin is the major binding protein, accounting for about 55 to 60% the binding, and 20% is bound to α1-acid glycoprotein. In addition, melphalan binding studies have revealed the existence of an irreversible component attributable to the alkylation reaction with plasma proteins.
In 28 patients with various malignancies who were given doses between 70 and 200 mg/m² body surface area as a 2 to 20 min infusion, the mean volumes of distribution at steady state and central compartment were, respectively, 40.2 ± 18.3 litres and 18.2 ± 11.7 litres.
Melphalan displays limited penetration of the blood-brain barrier. Several investigators have sampled cerebrospinal fluid and found no measurable medicinal product. Low cerebrospinal fluid concentrations (~10% of that in plasma) were observed in a single high-dose study in children.
The chemical hydrolysis of melphalan to monohydroxymelphalan and dihydroxy melphalan is the most important metabolic route in humans. These metabolites are inactive.
In vivo and in vitro data suggest that spontaneous degradation rather than enzymatic metabolism is the major determinant of the medicinal product’s half-life in man.
In 15 children and 11 adults given high-dose intravenous melphalan (140 mg/m² body surface area) with forced diuresis, the mean initial and terminal half-lives were found to be 6.5 ± 3.6 min and 41.4 ± 16.5 min, respectively. Mean initial and terminal half-lives of 8.8 ± 6.6 min and 73.1 ± 45.9 min, respectively, were recorded in 28 patients with various malignancies who were given doses of between 70 and 200 mg/m² body surface area as a 2 to 20 min infusion. The mean clearance was 564.6 ± 159.1 ml/min.
Melphalan clearance may be decreased in renal impairment (see sections 4.2 and 4.4).
No correlation has been shown between age and melphalan clearance or with melphalan terminal elimination half-life (see section 4.2).
Melphalan was mutagenic in Salmonella typhimurium. Melphalan caused chromosomal aberrations in vitro (mammalian cells) and in vivo (rodents). Clinical information on potential toxicity of melphalan is provided in sections 4.4 and 4.6.
Melphalan, in common with other alkylating agents, has been reported to be leukaemogenic. There have been reports of acute leukaemia occurring after melphalan treatment for diseases such as amyloid, malignant melanoma, multiple myeloma, macroglobulinaemia, cold agglutinin syndrome and ovarian cancer.
The potential therapeutic benefit when considering the use of melphalan must be balanced against the risk that may occur.
Melphalan was teratogenic in rats after single dose exposure in reproductive toxicity studies. In repeated dose reproductive toxicity studies, melphalan was maternal toxic and induced congenital malformations. A single dose of melphalan in male mice induced cytotoxicity and chromosomal aberrations in sperm cells. In female mice a reduction in number of pups per litter was observed. After recovery, the number of pups per litter was also reduced over time, which was related to a reduced number of follicles.
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