MELPHALAN

Fetal Risk Summary

Melphalan, a phenylalanine derivative of nitrogen mustard, is a bifunctional alkylating agent. No reports linking the use of melphalan with congenital defects have been located. The drug is mutagenic as well as carcinogenic (1,2,3,4,5,6,7 and 8). These effects have not been described in infants following in utero exposure. Although there are no supportive data of a teratogenic effect in humans, melphalan is structurally similar to other alkylating agents that have produced defects (see Chlorambucil, Mechlorethamine, Cyclophosphamide).

Reproduction studies in rats with oral doses of 6 to 18 mg/m2/day for 10 days, or with a single intraperitoneal dose of 18 mg/m2 revealed embryolethal and teratogenic effects (9). Congenital anomalies included the brain (underdevelopment, deformation, meningocele, and encephalocele), eye (anophthalmia and microphthalmos), reduction of the mandible and tail, and hepatocele.

Studies examining the placental transfer of melphalan have not been found. The molecular weight (about 305) is low enough, however, that transfer across the placenta to the fetus should be expected.

Data from one review indicated that 40% of the infants exposed to anticancer drugs were of low birth weight (10). Long-term studies of growth and mental development in offspring exposed to melphalan and other antineoplastic drugs during the 2nd trimester, the period of neuroblast multiplication, have not been conducted (11).

Melphalan has caused suppression of ovarian function resulting in amenorrhea (11,12,13 and 14). These effects should be considered before administering the drug to patients in their reproductive years. However, in 436 long-term survivors treated with chemotherapy between 1958 and 1978 for gestational trophoblastic tumors, 15 received melphalan as part of their treatment regimens (15). Three of these women had at least one live birth (mean melphalan dose 18 mg; maximum dose 24 mg), and the remaining 12 did not attempt to conceive. Complete details of this study are discussed in the monograph for methotrexate (see Methotrexate).

Occupational exposure of the mother to antineoplastic agents during pregnancy may present a risk to the fetus. A position statement from the National Study Commission on Cytotoxic Exposure and a research article on some antineoplastic agents are presented in the monograph for cyclophosphamide (see Cyclophosphamide).

Breast Feeding Summary

No reports describing the use of melphalan during lactation have been located. Excretion into breast milk, however, should be expected because of the relatively low (about 305) molecular weight. Because of the potential for severe toxicity in the nursing infant, women receiving this antineoplastic agent should not breast feed.

References

1. Sharpe HB. Observations on the effect of therapy with nitrogen mustard or a derivative on chromosomes of human peripheral blood lymphocytes. Cell Tissue Kinet 1971;4:501–4.
2. Kyle RA, Pierre RV, Bayrd ED. Multiple myeloma and acute myelomonocytic leukemia. N Engl J Med 1970;283:1121–5.
3. Kyle RA. Primary amyloidosis in acute leukemia associated with melphalan. Blood 1974;44:333–7.
4. Burton IE, Abbott CR, Roberts BE, Antonis AH. Acute leukemia after four years of melphalan treatment for melanoma. Br Med J 1976;1:20.
5. Peterson HS. Erythroleukemia in a melphalan treated patient with primary macroglobulinaemia. Scand J Haematol 1973;10:5–11.
6. Stavem P, Harboe M. Acute erythroleukaemia in a patient treated with melphalan for the cold agglutinin syndrome. Scand J Haematol 1971;8:375–9.
7. Einhorn N. Acute leukemia after chemotherapy (melphalan). Cancer 1978;41:444–7.
8. Reimer RR, Hover R, Fraumen JF, Young RC. Acute leukemia after alkylating agent therapy of ovarian cancer. N Engl J Med 1977;297:177–81.
9. Product information. Alkeran. Glaxo Wellcome, 2000.
10. Nicholson HO. Cytotoxic drugs in pregnancy: review of reported cases. J Obstet Gynaecol Br Commonw 1968;75:307–12.
11. Dobbing J. Pregnancy and leukaemia. Lancet 1977;1:11–15.
12. Rose DP, David PE. Ovarian function in patients receiving adjuvant chemotherapy for breast cancer. Lancet 1977;1:1174–6.
13. Ahmann DL. Repeated adjuvant chemotherapy with phenylalanine mustard or 5-fluorouracil, cyclophosphamide and prednisone with or without radiation. Lancet 1978;1:893–6.
14. Schilsky RL, Lewis BJ, Sherins RJ, Young RC. Gonadal dysfunction in patients receiving chemotherapy for cancer. Ann Intern Med 1980;93:109–14.
15. Rustin GJS, Booth M, Dent J, Salt S, Rustin F, Bagshawe KD. Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumours. Br Med J 1984;288:103–6.