British lournu! of Haernatology. 1992. 82, 3 5 4 - 3 5 ;

Low-dose etoposide: a potential therapy for myelodysplastic syndromes K. OGATA,T. Y A M A D AT. . ITO. S. G O M I , Y . T A N A B EI.. O H K I ,K. DAN A N D T . NOMURA The Third Department of lnternal Medicine, h’ippon Medical School. Seridagi 1-1 -5, Bunkyo-ku, Tokyo 1 1 3 . Japan Received 2 March 1992; rtcceptedfor publieation I I June 1992

Summary. Four patients with refractory anaemia with excess blasts in transformation (KAEB-t) and seven patients with acute leukaemia ALI transformed from myelodysplastic syndromes (MDS) were treated with etoposide ( 50 mg. 2 h infusion, two to seven times per week) for at least 4 weeks. Of 1 0 assessable patients. three RAEB-t patients achieved partial response and one AL patient achieved complete remission. Three of the four responders were resistant to prior repeated low-dose cytarabine therapy. The responders did not require

transfusions for 2-9 months while continuing on etoposide therapy. The side-effects were mild and well tolerated. Three possible mechanisms, i.e. a cytotoxic effect, differentiationinduction of malignant cells, and prolongation of blood cell survival by destroying the reticuloendothelial system, may explain the effects of etoposide. We conclude that low-dose etoposide is a potential therapy for MDS and atypical leukaemia.

Therapy for myelodysplastic syndromes (MDS) and acute leukaemia (AL) transformed from MDS is not well established. Allogeneic bone marow transplantation (BMT) seems to be the only curative therapy for young patients. if a suitable donor is available. The results of intensive chemotherapy are generally inferior to that ofdr n o w Al,. Although success in young cases treated with intensive chemotherapy has been reported, the remission durations were usually short (Tricot & Boogaerts, 1986: De Witte et a!, 1990). A considerable proportion of the patients responded to low-dose cytarabine (LDCA) therapy. but durable remissions are rare. and resistant or relapsed cases have a poor prognosis (Cheson et a/. 1986: Yamada rt al. 199 1 ). Etoposide (VP 16-21 3 ) has a broad spectrum of antitumour activity and has recently been shown to induce the differentiation of human leukaemic cell lines at low concentrations in vitro (Nakayaet ul. 199 1; Rius rt (11. 199 1 ). In this study. we used low-dose etoposide to treat 1 1 patients who had refractory anaemia with excess blasts in transformation (RAEB-t) and AL transformed from MDS.

consent. Disease diagnoses were made according to the standard criteria (Bennett et a/. 1982). Unless otherwise stated, 50 mg ofetoposide (24-3 7 mg/mL)was given (i.v., 2 h infusion) two to seven times per week. The frequency of etoposide administration per week was decided based on each patient’s blast mass and the degree of neutropenia. When severe neutropenia developed, the therapy was withheld for 1-3 weeks and then reinstituted. The treatment was conducted for at least 4 weeks, and was continued longer in responders. Erythrocyte and platelet transfusions were given to maintain the Hb above 6 g/dl and the platelet count above 2Ox 1OY/I. The response to therapy was defined as (1) complete remission (CK): normocellular bone marrow containing O-So/, blasts and normal levels of erythroid and granuloid series, accompanied by normal levels of peripheral WBC and platelets with no circulating blasts, (2) partial response (PR): normalization of the peripheral blood cell count, or elimination of all transfusions with Hb. neutrophils, and platelets remaining above 6 g/dl. 0 . 5 x 1OY/1 and 2 0 x 1 0 y / l , respectively, for at least 2 months, or ( 3 ) early death: died within 3 weeks after the initiation of therapy. Toxicity was defined according to the World Health Organization (WHO) criteria (Miller et a!, 1981).

METHODS

Eleven patients (four with RAEB-t and seven with AL following MDS). were included in this study after informed

K ESU LTS Table I shows a profile of the patients and their response to etoposide. No patients had a significant monocytic component as revealed by cytochemical and lysozyme analyses

Correspondence: Dr Ktyoyukt Ogata. The Third Department of Internal Medicine Nippon Medical School. Sendagi 1 - 1 - 5 . Bunkyoku. Tokyo 113 , japan.

3 54

3 55

Low-dose Etoposide Therapy for MDS Table 1. Patient profile and the response to etoposide therapy. Haematologic data before etoposide therapy Peripheral blood

Age/Sex

Diagnosis

Hb (g/dl)

1 2 3 4 5 6 7 8

41/M 73/M 42/M 5 7/F 68/M 21/M 73/M 62/F

AL RAEB-t RAEB-t RAEB-t RAEB-t RAEB-t AL AL

4.6 5.8 5.9 10.0 5.0 5.8 7.0 13.0

9

69iF

AL

10

47/M 74/F

AL AL

Patient

11

Bone marrow

Neutrophils ( x 10y/l)

Platelets ( x 1OY/1)

Cellularity

1.10 6.00 0.20 0.70 0.06 0.01 1.50

3 10 70 9 130 15 9 30

54 12 73 57 66 25 5 29

5.0

0.80

7

70

8

6.0 4.8

0.20 0.02

20 4

80 65

94 70

0

(%)

Blasts (%) 10

-

Response (duration):

Survivalt

NR

46

Previous therapy LDCA LDCA

14 6

-

-

-

49 64 15

LDCA LDCA, BHAC-DMP, A-Triple-V. BHAC-EM BHAC-DMP. A-Triple-V LDCA

LDCA

-

NR Early death

4.5 1

Bone marrow cellularity was determined in histological sections of bone marrow aspirate or trephine biopsy. Chemotherapy with LDCA. BHAC-DMP (behenoyl cytosine arabinoside, daunorubicin. 6-mercaptupurine, prednisolone), BHAC-EM (behenoyl cytosine arabinoside. etoposide. mitoxantrone), and A-Triple-V (cytosine arabinoside, etoposide, vincristine, vinblastine) was performed according to methods described in previous reports (Yamada et a!, 1991; Ohno eta!, 1986, 1990; Sauter et al. 1982). *tDuration of response and survival from the time of diagnosis of RAEBt or AL are expressed in months.

LDCA

1 0

LDCA

LDCA

LDCA

Etoposide

0 0 0 CR

Platelets

Hb

( x 1o9ia) (0-J)

30

Neutrophils

( x 10 - i ~ ) (-1

Pig 1 . Clinical course of the AL patient (No. 1 ) who was refractory to four courses of LDCA and obtained CR with low-dose etoposide.

during their entire clinical course. No patients had received any cytotoxic therapy before their disease progressed to RAEB-t or overt leukaemia. The young patients had no suitable donor for BMT. Case 1 had AL accompanied by anaemia, thrombocytopenia and a diffuse ulcer, considered to be leukaemic infiltration, on the right leg. He was initially treated with four courses of LDCA. Although the percentage of leukaemic blasts in the bone marrow decreased, the

cytopenia persisted and the ulcer worsened during each interval between LDCA courses. Subsequently he was given etoposide. His cytopenia and ulcer improved gradually, and CR was attained on the 46th day of etoposide therapy (Fig 1). Myelodysplasia and a chromosome abnormality (46XY, t(6;9) (p23;q34)), which had been detected before the therapy, disappeared. The leukaemia relapsed 4 months after obtaining CR, despite receiving consolidation chemotherapy

3 56

K. Ogata et a1

with mitoxantrone ( 6 mg/m’. 5 d ) and etoposide (100 mg/ m2, 3 d ) .Case 2 had RAEB-t with pancytopenia. myelolibrosis and circulating blasts (20-300/, of the WBC). He failed to respond to three courses of 1DCA and so was given etoposide for 8 weeks. After the requirement for transfusions decreased. the etoposide administration was changed to oral. Following 6 months treatment. the blood cell counts were completely normal with no circulating blasts. but myelofibrosis persisted. His peripheral blood picture remained normal for another 6 months on oral etoposide. but he died of intracranial haemorrhage. Case 3 had RAEB-t. accompanied by anaemia. thrombocytopenia. and high fever considered to be tumourderived. He was initially treated with 5 0 mg of etoposide for 3 weeks and then the dose was reduced to 2 5 mg. Following 8 weeks of treatment, the fever disappeared and the blood cell counts were normal. He remained in good condition on etoposide until 3 months later, when bone marrow blasts increased. He died of infection after receiving LDCA. Case 4 had RAEB-t accompanied by transfusion-dependent thrombocytopenia. Her disease was resistant to three courses of LDCA, so she was given etoposide. The requirement for platelet transfusions gradally decreased, and none was needed 5 weeks later. Despite continued etoposide therapy. platelet transfusions became necessary again 2 months later. As toxicities. nausea (WHO grade 1 ) and alopecia (WHO grades 2 and 3 ) were seen in three and six patients. respectively. Since all patients had cytopenia before treatment. myelosuppression could not be properly assessed. Neutrophil and platelet counts decreased during the therapy in five and two patients. respectively. but returned to the pretreatment levels 1-3 weeks after discontinuation of the therapy. except for Case 1 I , who died of infection on the 1 7th day of the therapy.

111sCU s s I O N Recently, Oscier et NI ( 1989 J reported oral low-dose etoposide ( 50 or 100 mg. two to seven times per week) was effective for patients with chronic myelomonocytic leukaemia. In this study we used low-dose etoposide therapy for patients with KAEB-t and AL who were likely to die rapidly if chemotherapy was ineffective. Etoposide was given intravenously. since oral etoposide has considerable inter- and intra-patient variation in its bioavailabilitp (D’Incalci et (71. 1982; Harvey et nl. 1985).It is noteworthy that three of the four responders had been resistant to at least three courscs of LDCA. The toxicities that developed were mild and well tolerated. The beneficial response of etoposide did not appear particularly rapidly. Although the leukaemic skin lesion and MDS-derived fever began to resolve after 1-2 weeks of therapy in Cases 1 and 3 . blood cell counts took 30-50 d to increase in Cases 1 4. The total dosage of etoposide by the time of improvement was 1 100. I 600. 800 and 1000 mg in Cases 1-4, respectively. The mechanisms underlying the response to etoposide therapy may be heterogeneous. The bone marrow of Case 1 could not be examined until he attained CR. However, the development of transient leucopenia during the therapy and the bone marrow normalization in morphology and karyotype indicate that etoposide suppressed the abnormal clone.

In Cases 3 and 4. bone marrow cellularity was not reduced and the blood cell counts increased despite the continued administration of etoposide. These findings suggest two possible mechanisms. The first is induction of the differentiation of malignant cells and the second is that etoposide prolongs the survival of blood cells by destroying the reticuloendothelial system, as proposed by Wood & Jacobs ( 1988). who successfully treated a patient with idiopathic thrombocytopenic purpura with etoposide-loaded platelets. We conclude that low-dose etoposide is a potential therapy for RAEB-t and AL transformed from MDS, even when patients are resistant to other regimens. Since this therapy is well tolerated and can reduce the requirement for transfusions in some cases, it is worth considering when repeated transfusions are required in other MDS subtypes. ACKNOWLEDGMENT \Z’e thank the medical and nursing staffs for their invaluable help. REFEKENCES Bennett. J.M.. Catovsky. D.. Daniel, M.T.. Flandrin. G.. Calton, D.A.C.. Galnick, H.R. & Sultan, C. (1982) Proposals for the classification of the niyelodysplastic syndromes. British Journal of’ Hnerrintologg. 5 1 . 189-199. Cheson. B.D.. /asperse. D.M.. Simon. R. & Friedman, M.A. (1986) A critical appraisal of low-dose cytosine arabinoside in patients with acute non-lymphocyticleukemia and myelodysplastic syndromes. jo~rrrinlof Ciinicnl Onrology. 4,1857-1 864. Ile b‘itte. T.. Muus. P.. De Pauw. H. & Haanen. C. (1990) Intensive antileukernic treatment of patients younger than 65 years with myelodysplastic syndromes and secondary acute myelogenous leukemia. Cnnrvr, 66, 831-837. D’Incalci. M.. Farina. P.. Sessa. C.. Mangioni, C.. Conter. V.. Masera. G., Rocchetti. M.. Bramhilla Pisoni. M.. Piazza, E., Beer, M. & Cavalli. F. (1982) Pharmacokinetics of VPlh-213 given by different administration methods. Cancer CIivniotherapy and Pharrnnroloy!j. 7, 141 -1 4 5. Harvey. L’.J..Slevin. MA.. Joel. S.P..Johnston. A. & Wrigley. P.F.M. ( 1 9 8 5 ) The effect of food and concurrent chemotherapy on the bioavailability of oral etoposide. British lournui of’Canrer, 52, 36336i.

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