Could Melphalan be Useful for Elderly Patients with Myelodysplastic Syndrome or Secondary Acute Myelogenous Leukemia?

Abstract & Commentary

Source: Denzlinger C, et al. Br J Haematol 2000;108:93-95.

Myelodysplastic syndrome (mds) and secondary acute myelogenous leukemia (sAML) are diseases with few satisfying treatment options. In this study from Germany, 21 patients with MDS or sAML were treated with oral melphalan 2 mg each day. If progressive disease occurred after four weeks of treatment, patients were taken off study. Melphalan was held in cases of a complete peripheral response, and was restarted upon relapse.

The patients’ ages ranged from 59 to 84 years with a median of 71 years. Patients were classified according to the French-American-British (FAB) classification as having the following subtypes: chronic myelomonocytic leukemia (CMML) (n = 1), refractory anemia with excess blasts (RAEB) (n = 8), refractory anemia with excess blasts in transformation (RAEB-t) (n = 5), or sAML (n = 7). A complete peripheral response required a hemoglobin (Hb) more than 12, platelet count more than 100,000, neutrophil count (ANC) more than 1500, and the absence of blasts. A partial peripheral response was not precisely defined but only two patients fell into this category.

Pretreatment patient characteristics were presented in a table, including the blood counts, karyotype, bone marrow cellularity, percent blasts in the bone marrow, and FAB subtype. Patients with sAML had blast counts that ranged from 35-90%. The mean pretreatment Hb, platelet count, and ANC were 8.3, 54,000, and 700, respectively. The cellularity of the bone marrow was described as normal, hypo-, or hypercellular, with no strict definitions of these three categories provided. Nevertheless, no patient with a hypercellular marrow or a complex cytogenetic karyotype responded to melphalan. By excluding these patients, a subgroup of patients with MDS or sAML was identified that collectively had a response rate of 75% (9/12 patients).

Within 4-16 weeks, there were seven complete and two partial peripheral responses. In all of these patients, improvement was noted within the first month. The responses in peripheral blood counts lasted for a median of 25 weeks (12+ to 55). All five patients characterized as having a complete response were retreated upon relapse, although exact criteria for relapse were not presented. Four of them again achieved a complete response lasting 18 to 53+ weeks. Overall toxicity was described as mild, consisting of a transient worsening of cytopenias, but no infectious or bleeding episodes requiring hospitalization.

COMMENT by Kenneth W. Kotz, MD

This is an interesting report because melphalan, a drug that has long been available, has not been considered a treatment option for patients with MDS or sAML. Denzlinger and colleagues pursued this approach based on a single prior report from Japan.1 In that report, the decision to try melphalan in MDS was based on activity seen with a conjugate of human IgG and melphalan that may accumulate more selectively and last longer in malignant cells. When activity was seen, it was then hypothesized that the activity of the conjugate in MDS could be reproduced with melphalan alone.1 In fact, of the 21 patients (median age, 65 years) with MDS (6 with RAEB and 15 with RAEB-t) receiving melphalan at 2 mg a day, an astonishing 12 patients responded (7 complete), with a median duration of response of 14.5 months. They also observed negligible toxicity.1

It is not known whether the total response time would be longer with intermittent or continuous melphalan administration, as was done in the studies from Germany and Japan, respectively. In the study by Denzlinger et al, most complete responders did respond again when rechallenged but it is not clear from the article how long patients were followed off therapy after their first response. Therefore, a "total response" time cannot be calculated. As mentioned, patients with complex cytogenetic changes and hypercellular marrows did not respond at all. However, the classification of the underlying disease was not predictive of a response, as patients with both MDS (6/14) and sAML (3/7) responded. Denzlinger et al plan a placebo-controlled, prospective clinical trial restricted to those with normal or reduced bone marrow cellularity.


1. Omoto E, et al. Leukemia 1996;10:609-614.

Regarding the study of MDS and sAML, which one of the following is true?

a. Patients with a hypercellular bone marrow responded well to melphalan.

b. Patients with MDS responded better to melphalan than patients with sAML.

c. Responses to melphalan occurred only at high doses.

d. Improvement was usually noted within a month in patients who responded.