I I

Low Dose Cytosine Arabinoside in the Treatment of Myeloid Leukaemias and Myelodysplastic Syndromes

M. Mm-my, P. Sarsfield; E. Lawior and. S. R. McCmm

Departmem of Clinical Haematology / Oncology, St. James's Hospital and Trinity College Dublin, Ireland.

Summary

WELVE patients were treated T . �9 .

with low-dose cytosine arabinos- ide (15 mg/m2). Eight patients had acute myeloid leukaemia (AML), two llad myelodysplastic syndromes (MDS) and two patients had myelo- fibrosis. Three patients with AML achieved a complete remission (CR), and one patient achieved CR fol'ow- ing the addition of COAP (cyclo- phosphamide, vincristine, cytosine arabinoside, prednisone). Two pat- ients with MDS achieved & CR, one patient requiring the addition of COAP. One of two patients with myelofibrosis showed a partial re- sponse to, treatment. All patients required intensive platelet sup~r t but infections were few. Low-dose cytosine arabinoside should be con- sidered as initial therapy in elderly patients with AML and MDS. Its role in myelofibrosis remains to be established.

Introduction

Acute myeloid leukaemia (AML) occurs with increasing frequency in the older age groups. Nearly 40% of patients with AML are over sixty years of age. Many of these patients have co-existent medical problems which may make them less tolerant of intensive cyto-reductive regimens.

Sixty to eighty percent of patients with AML achieve a complete re- mission (CR) ~. Remission rates in patients over sixty years of age vary from 30% to 62% ~. The poor toler- ance of the elderly to the side effects of intensive chemotherapy, such as mucositis and associated infections, may have led to the undertreatment of this group of patients and increase their risk of death during attempted

Correspondence : S. R. MeCann, Department of Clinical Haernatology/Oncology, St. James Hospital, Dublin 8, Ireland.

remission induction 3,4. The mean survival of those patients who ach- ieve a complete remission is 22 months 2. Twenty-five percent of patients achieve a second remission with a mean survival after relapse of approximately six months, but 10- 40% of these will have an extended disease free survival, once their re- mission has been achieved ~. Myelo- dysplastic syndromes (MDS) in the elderly and myelofibrous (MF) do not appear to respond to intensive chemotherapeutic regimens.

Low dose cytosine arabinoside (L-DAC) has been shown to be effective in a wide range of diseases, with minimal toxicity. We report here, our experience with its use in the treatment of AML, MDS and MF.

Patients, Materials and Methods

Twelve adult patients were treated in St. James's Hospital, Dublin (Table I). There were eight male and four female patients. The age range, of the twelve was from 53-79 years. Four patients had AML and had received no previous chemother- apy. Their average age was 70 years.

F o u r patients had relapsed AML. Two of these were in their first re- lapse and the remainder in second or subsequent relapse. Their average age was 65 years. Two patients had MDS. One, was a 79 year old man, with refractory anemia and excess blasts (RAEB) and the other a 75 year old man with a myeloid trans- formation of chronic myelomono- cytic leukaemia (CMMoL). Two patients had MF. Both had devel- oped MF following treatment of a myeloproliferative disorder. One had received 32p therapy for polyeythemia ruba vera (PRV). The second pat- ient had received intermittent busul- fan therapy for primary thrombo- cythemia during the preceding 19 years.

Trealment Schedule

Cytosine arabinoside was adminis- tered subcutaneously at a dose of 15 mg/m 2 every 12 hours (L-DAC). Response to treatment was evaluated by weekly examination of bone mar- row aspirates. Treatment was dis- continued if the bone marrow became hypoplastic or was changed to COAP (Table I) if the disease persisted.

Those l~tients who achieved a complete remission (CR) subsequen- tly began maintenance treatment with cytosine arabinoside 15 mg/m~ sub- cutaneously twice daily for five consecutive days each month.

The patients were nursed in an open haematology ward. Venous access was via a peripheral line in all patients at the commencement of treatment, but was subsequently changed to a central venons line in four patients. Patients were sup- ported with leucocyte-Ix)or red cell transfusions to maintain a haemo- globin at greater than 10 g/dl s. Random donor platelets were given when the platelet count fell below 20 x 10~ftitre and there was a tem- perature greater than 38~ or evidence of bleeding.

Remdts Three of the eight patients with

AML achieved CR. A fourth patient who failed to respond after 38 days of L-DAC achieved a CR following the addition of a course of COAP (Table I). Remission duration ran- ged from 6 to 17 months with a mean of 10 months.

Two further patients with AML failed to respond to L-DAC and both achieved a partial remission (PR) following one course of COAP (Table I).

Patient no. 9 with MDS (RAEB) achieved a CR of 4 months duration, following 28 days of L-DAC. He

238

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VoL 157 Treatment o[ Myeloid Leukaemi~zv No. 7

TABLE I

Prior UPN Sex Age Treatment Diagnosis Treatment Outcome

1 M 77 No AML L-DAC 14 days CR 17 months maintenance L-DAC

2 F 63 Yes AML L-DAC 15 days CR 7 months. Died relapsed maintenance L-DAC leukaemia

3 M 72 Yes AML L-DAC 28 days CR 6 months. Died relapsed maintenance L-DAC leukaemia

4 F 67 No AML L-DAC 38 days CR relapsed at 6 months. COAP x 1 Died refractary leukaemia L-DAC maintenance

5 F 66 No AML L-DAC 28 days PR 4 months COAP x l Died leukaemia maintenance L-DAC

6 M 69 No AML L-DAC 28 days PR 4 months COAP x 1 Died leukaemia maintenance L-DAC

7 M 71 Yes AML L-DAC 23 days

8 F 62 Yes

9 M 79 No

10 M 75 No

11 M 59 Yes

12 M 53 Yes

239

COAP

CR

P R

N R

PRV

MF

AML L-DAC 12 days

RAEB L-DAC 16 days

CMMoL L-DAC 21 days (Acute transformation) COAP x 1

MF L-DAC 15 days PRV

Thrombocythaemia L-DAC 20 days MF

= Cyclophosphamide Vincristine Cytosine arbinoside Prednisone

= Complete response

- - 600 mg/m 2 i.v. day I - - 1.5 mg/m 2 i.v. 'dj~ 1

- - 100 mg/m 2 i.v. days 1-5 - - 60 mg/m 2 PO days 1-5

NR. Died staphyloccus aureus septicemia, persistent leukemia

NR. Died persistent leukemia

CR 4 months. Relapsed Died~ C.V.A.

CR 8 months. Died pneumonia leukemia in CR

PR 4 months. Died With AML

NR

= Partial response. Fifty percent reduction in bone marrow blast count or normalization of peripheral blood. i.e. Hb > 10 gm/dl, platelets > 50 x liFL, WCC > 2.0 x 109/L and transfusion independent.

= No response

= Polycythemia rubra vera

= Myelofibrosis

died at home fol lowing a second course of L - D A C given for relapse of RAEB. The second pat ient with MDS (CMMoL) achieved a C R following oaae course of C O A P hav- ing failed to respond to 21 days of L - D A C (Table I). H e died of pneu- m o n i a 8 months later wi thout evid- ence o,f leukemic relapse at autopsy.

Of the two pat ients with M F one achieved a P R after 15 days of L-DAC, i.e. reduct ion in spleen size,

decreased marrow fibrosis, decreased t ransfusion requirement and a rise in both platelet and white cell counts. F o u r months later he developed A M L and was unresponsive to high dose chemotherapy.

Two patients with relapsed A M L and one patient with secondary M F showed no response to t reatment (Table I).

Al l patients developed significant cytopenias requiring both platelet

and red cell transfusions (Table II). The average n u m b e r of platelet uni ts required per pat ient was 61 donor units with a range of 24-112 units and the average n u m b e r of red cell concentrates was 23 units with a range of 6 to 87 units.

~ n

Cytosine arabinoside, a cell cycle specific pyr imidine analogue, with a short p lasma half life has been used

240 Murray et al.

TABLE 1I

UPN Complications

Total RBC Units

Total Units

Platelets Antibiotics

1 Thrombocytopenia 17 2 Thrombocytoptnia 14 3 Thrombocytopenia 7 4 Thrombocytopenia 16 5 Thrombocytopenia UTI 19 6 Thrombocytopenia 19 7 Staph. septicemia 6

8 Thrombocyopenia 15 9 Thrombocytopenia 28

l0 Pyrexia, pulmonary 20 infiltrates

l I Thrombocytopenia 28 12 Thrombocytopenia 87

pyrexia

96 No 36 No 24 No 72 Yes for UTI 60 Yes for UTI 24 Yes Febrile neutropenic episode 30 Yes Febrile neutropenic episode 36 No

48 Yes Febrile neutropenic episode 112 Yes Febrile neutropenic episode

48 No

89 Yes Febrile neutropenic episode

with effect since the late 1960's in the treatment of acute myeloid leuk- emia (AML) 6. It has proved clinically successful in a wide range of doses and schedules ranging from 3 gin/ m 27 to 10-20 mg /m 28. Ultra low dose ARA-C 5mg/m 2 twice daily subcut- aneously may also be beneficial in the management of AML 8.

Recent reports have shown var- iable efficacy of low dose ARA-C (L-DAC) in the elderly leukemic population 8,16. Tilly et al reported a 50% complete remission rate (15/ 30), with a duration of remission greater than nine or ten months in many of these patients. The mean age of his group was, 73 years of age but all were previously untreated patients g. Ishikura obtained better results (CR 7/9) in a smaller but similar group. Poor results are re- ported by groups with a high pro- portion of previously treated and relapsed patienLs al, 12.

Armitage et al felt that aggressive chemotherapy was hOe only ineffect- ive, but could even shorten the life span of patients with myelodysplastic syndromes aS. Variable results have been reported by different groups using low-dose ARA-C in MDS. Tricot treated 26 patients with MDS, all showing acceleration, of their disease 1~. Only 3/26 patients achieved

a complete remission, though a r~ SlXmse in peripheral blood counts was seen in 50% of patients. Most of the patients who had shown a good response had received more than 750 mg of ARA-C. In a series of patients by Worsley et al 5 of 22 patients with MDS and AML showed a reslXmse s.

A single case report by Whitehead showed the efficacy of low-dose ARA-C in reducing fibrosis and normalizing the peripheral cell counts in a middle aged man with acute myelofibrosis a~. We treated two patients with MF, one of whom showed a partial response (Table I).

Treatment was well tolerated by all patients. There was no mucositis or associated gastrointestinal toxic- ity. Patchy alopscia was experienced by one patient. All patients devel- oped significant neutropenia and thromboeytopenia, with a mean duration in those who responded (9/12) of 45.5 days and 37 days respectively. Severe thrombocyto- penia (<20 x lIT/D, maximal in the second week has been widely rep0r- ted, and has in some cases been associated w i ~ severe bleeding and cerebrovaseular accidents u. Two episodes of bleeding were seen in our patients, one in association with previously diagnosed pep t i c ulcer

I J .M.S . July. 1988

disease and one as a complication of disseminated intravascular coagula- tion. The relatively low incidence of septicemia following L-DAC (1 of 12 patients) may reflect the absence of mucositis and the infrequent use (4/12) of indwelling central venous lines.

The frequency of pancytopenia and support care necessary with this form: of treatment emphasises the need for close monitoring, specialist care, and the availability of trans- fusions facilities. More than 50% of patients with A ML could achieve a complete remission without an over- night stay in hospital s .

The mechanism of action of ARA -C is controversial with conflicting evidence supporting its role as a differentiating agent or as a eytotoxie agent. Sachs et al have demonstrated its ability, in vitro, to cause differen- tiation of leukemic cells a6. Ishikura showed confleting evidence when he demonstrated differentiation, using short term cultures, in four patients but the remaining five did not show any evidence of differentiation TM.

Leyden demonstrated no evidence of differentiation TM. The slow evolution in some series of complete remission has been used to favour its role as a differentiating agent 17.

Low dose ARA-C is effective treatment for AML in elderly pat- ients and should be considered as a therapeutic option in this group. Its therapeutic role in the treatment of MDS and MF has still not been established.

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Treatment of Myeloid Leukaemias

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