American Journal of Hematology 39:6142 (1 992)

Low-Dose dnterferon Treatment of Chronic Myeloid Leukemia

Angel Sanchez, William A. Robinson, Allen Cohn, Rene Gonzalez, and Arun Adlakha Leukemia Research Clinic and Division of Medical Oncology, University of Colorado Health Sciences Center, Denver

We treated 29 patients with chronic-phase and accelerated chronic myeloid leukemia (CML) with a-interferon in a dose of 2 mU/m2 given subcutaneously daily for 30 days and then three times per week. Most had received prior treatment. Three patients have had sustained hematologic and karyotypic remissions after a median of 22 months of treat- ment. Three further patients have had complete hematologic and partial karyotypic remis- sions. At a median follow-up of 48 months, the median survival has not been reached. This dose of a-interferon may induce sustained remissions even in pretreated patients and may prolong survival in CML.

Key words: CML, IFN, Philadelphia chromosome

INTRODUCTION

The ability of a-interferon to induce hematologic and karyotypic remissions in patients with chronic myeloid leukemia (CML) has been demonstrated by Talpaz et al. [l] and others [2,3]. Hematologic remissions can be achieved in 70% of patients and 30% of these have signif- icant karyotypic responses. The dose of a-interferon used has been associated with considerable toxicity in most studies. Based on previous studies with low-dose inter- feron therapy in hairy cell leukemia [4], we undertook a study to evaluate the benefit of low-dose a-interferon in CML.

MATERIALS AND METHODS

Twenty-nine patients (1 8 males and 1 1 females) were treated with recombinant a,,-interferon in a dose of 2 mU/m2 self-administered subcutaneously daily for 30 days and then three times per week. Hydroxyurea was used initially to control leukocytosis when the white blood cell (WBC) count was above 50 X lo3 pl. The median age was 40 years (range 24-67 years). Twenty- seven were in chronic phase, and two were in accelerated phase. Twenty-seven had received prior treatment. All of these had received hydroxyurea and seven busulfan. Six had been treated previously with y-interferon, with no response. Twenty-four had been treated for more than 1 year. The median time from diagnosis to starting inter- feron was 22 months (range 1-72 months). All patients were Philadelphia chromosome positive (Ph+), with

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100% of bone marrow metaphases containing the translo- cation. The median hematologic parameters at initiation of therapy were WBC, 33.9 X 103/pl, Hb 13.1 g/dl, platelets 408 X 103/pl. Patients were followed every 3 weeks, and bone marrow biopsies were performed when peripheral hematologic values were normal and then ev- ery 6 months thereafter. Duration of survival was calcu- lated from the time of diagnosis.

A complete hematologic remission was defined as nor- malization of peripheral WBC and differential counts, with disappearance of all clinical signs of disease. A partial hematologic remission was defined as a sustained decrease in the WBC from pretreatment values to less than 20 X 103/pl; progressive disease was defined as the development of blast crisis. A complete cytogenetic re- sponse was defined as 100% normal metaphases on at least two occasions 6 months apart. A partial cytogenetic response was any decrease in Pht cells on two or more occasions.

RESULTS

The remission rates of the 29 patients treated in this study are shown in Table I. After a median treatment

Received for publication June 20, 1991; accepted August 15, 1991.

Address reprint requests to William A. Robinson, MD, PhD, Division of Medical Oncology, University of Colorado Health Sciences Center, 4200E. 9th Avenue, Box B171, Denver, CO 80262.

62 Brief Report: Sanchez et at.

TABLE 1. Remission Rates at Median Follow-Up of 48 Months of 29 Patients With CML Treated With Low-Dose dnterferon

Remission

Hematologic Cytogenetic

No. Percent No. Percent

Complete 7 24 3 10 Partial 5 17 3 10

Stable 8 28 Progression 9 31

Total response 12 41 6 20

duration of 22 months, seven of 29 patients (24%) have achieved a complete hematologic remission and five ( 1 7%) partial hematologic remission, for a total response rate of 41%. Three patients (10%) have had complete, sustained karyotypic remissions. Two of these were pre- viously treated and have been diagnosed for over 2 years. Three others have had partial karyotypic remissions. Eight patients (28%) have had stable disease, and nine have had progressive disease, and six of them have died. At a median follow-up of 48 months (range 11-100 months) from initial diagnosis, 20 (69%) of the patients remain alive and on treatment; the median survival has not been reached.

study due to toxicity. The response rate is lower than that reported by other investigators, probably due in large part to the fact that these were mostly previously treated pa- tients. Our data also suggest that there may be prolonged survival in such patients, although further follow-up is necessary before this can be confirmed. Based on the observations presented here, we believe that a trial of low-dose a-interferon in previously untreated patients with CML is indicated and may achieve results seen in other series with higher doses and greater toxicity.

ACKNOWLEDGMENTS

We thank the CRC staff nurses of University Hospital for their care of the patients and Sharon Byrne for typing the manuscript. This study was supported by grant R-00051 from the General Clinical Research Center of the National Institutes of Health, the Monfort Founda- tion, and Audrey Meyer Mars International Fellowship in Clinical Oncology from the American Cancer Society (A.S.).

REFERENCES

DISCUSSION

The present study indicates that low-dose a-interferon administered subcutaneously can induce hematologic and karyotypic remissions in patients with chronic-phase CML. The side effects of this dose of a-interferon were minimal, consisting primarily of fever occurring a few hours after administration, myalgias, fatigue, and occa- sional mild alopecia. No patient was withdrawn from the

I , Talpaz M, Kantarjian H. McCredie K , et al.: Hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha, in chronic myelogenous leukemia. N Engl J Med 3 14: 1065- 1069. 1986.

2. Freund M. von Wussow P, Diedrich H, et al.: Recombinant human interferon (IFN) alpha-2b in chronic myelogenous leukaemia: Dose dependency of response and frequency of neutralizing anti-interferon antibodies. Br J Haematol 72:350-356, 1989.

3. Thaler J , KuhrT, Gastl G, et al.: Rekombinantes Interferon alpha-2c bei Ph-positiver chronischer myeloischer Leukamie. Deutsch Med Wochenschr I16:721-728, 1991.

4. Smalley R, Tuttle R, Whisnant J , Anderson S , Huang A, Connors J , Robinson WA, et al.: Effectiveness of alpha-n-l at an ultra low dose in the treatment of hairv cell leukemia (HCL). Proc ASCO 6: 155. 1987.