Induction and maintenance alpha-interferon therapy in myelofibrosis with myeloid metaplasia

Barosi G, Liberato LN, Costa A, Buratti A, Di Dio F, Salvatore S , Ascari E. Induction and maintenance alpha-interferon therapy in myelofibrosis with myeloid metaplasia. Eur J Haematol 1990: 45: Suppl. 52: 12-14.

Abstract: In 12 patients having myelofibrosis with myeloid metaplasia (MMM), recombinant- a interferon (r-aINF) was given for 16 weeks at an initial dose of 3 x lo6 U/day as a cytoreductive agent. At the end of the 16th wk, Hb showed minor changes; WBC were reduced from 43 x 109/1, range 6.4-69.4, to 16 x 109/1, range 5-39 (p=0.05); platelets decreased from 845 x 109/1, range 215-1748, to 370 x 109/1, range 96-730 (p = 0.005). 2 cases responded at the starting dose, while the effective dose was 5 x lo6 U/d in the others. Minor changes in spleen size were noted, while no significant changes in bone marrow fibrosis occurred. After induction therapy, 3 patients were allocated to maintenance therapy (from 10 up to 34 months). To maintain platelet count lower than 500 x 109/1, the required r-a-INF dose was constantly 10 MU/wk, while the same result was not achieved in 1 case with hydroxyurea, 1 g/die. The association with hydroxyurea, 500 mg/die, allowed reduction of the r-aINF dose to 6 MU/die in 1 other case.

Introduction

In myelofibrosis with myeloid metaplasia (MMM) the peripheral blood picture ranges from refractory cytopenia to an excess number of circulating blood cells (1). Different bone marrow pictures have also been described, ranging from hypercellularity with an excess of megakaryocytes to virtual depletion of the hematopoietic elements associated with large degrees of fibrosis, and sometimes osteosclerosis (2, 4). As a consequence, therapy has to be chosen according to the hematologic and clinical picture

Recombinant-a interferon (r-a INF) is an ap- pealing therapeutic agent for MMM because, in vitro, it has shown an inhibitory effect on the growth of hemopoietic progenitor cells, especially megakaryocyte-committed stem cells (6-8), and bone marrow fibroblasts (9), the lineages thought to be implicated in the pathogenesis of this disease. Recently (lo), we reported that r-a INF acted as a cytoreductive agent in the induction, short-term therapy of 8 patients with MMM, especially for cases with thrombocytosis.

We now report clinical and laboratory results of both induction and maintenance r-aINF therapy

(5).

G. Barosi, 1. N. Liberato, A. Costa, A. Buratti, F. Di Dio, S. Salvatore and E. Ascari Diparlimento di Medicina lnterna e Terapia Med- ica (Sez. Clinica Medica 2), IRCCS Policlinico S. Matteo, 27100 Pavia, Italy

Key words: recombinant alpha-interferon - myel- ofibrosis with myeloid metaplasia - cytoreduction

Correspondence: Dr. Giovanni Barosi, Clinica Me- dica 2, IRCCS Policlinico S. Matteo, 27100 Pavia,

I Italy

in a larger number of patients having hypercytosis associated with MMM.

Patients. 14 patients, selected from 38 consecutive cases of MMM attending our department from January 1987 to June 1989 were considered eligible for treatment with r-aINF. In all cases, the diag- nosis was established according to the conventional criteria: increased medullary reticulin, splenomeg- aly, aniso- and poikilocytosis, leukoerythroblastos- is and teardrop cells. In all patients, a cytogenetic search of peripheral blood was made and the ab- sence of the Philadelphia chromosome was proved. Leukocyte alkaline phosphatase score ranged from 83 to 179 (normal range=40-130). The criteria used to include the patients in the study were the following: a bone marrow biopsy showing a hyper- cellular marrow; a platelet count greater than 500 x 109/1 and/or WBC greater than 10 x 109/l.

All patients were required to have a Karnofsky scale performance status of 2 50%. Adequate renal function (serum creatinine <2.0 mg/dl) and ad- equate hepatic function (bilirubin < 1.5 mg/dl) were also required. Written informed consent was

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Interferon in myelofibrosis

patients, the effective dose for response was 5 x lo6 U/d.

The treatment was associated with a reduction or disappearance of splenomegaly in 6 out of 9 patients (median reduction= 3 cm, range 0-3.5). No evaluable reduction in bone marrow fibrosis was observed in the 8 patients in whom bone mar- row biopsy was obtained at the end of treatment.

obtained from all patients before their partici- pation in the study began.

2 of the patients experienced severe side-effects and stopped treatment after the first few days of therapy. 12 patients underwent induction treatment for 4 months. In 3, maintenance r-a-INF therapy was then continued for 10 to 34 months.

The patients (8 males and 4 females) ranged in age from 34 to 70 years (median 52). The median time from diagnosis to initiation of r-aINF treat- ment was 3.8 yr (range 3 months to 15 yr). 2 of the patients had received prior chemotherapy or 32P treatment for polycythemia Vera; 3 had been splenectomized for symptomatic splenomegaly. The interval between prior cytostatics and r-aINF was at least 4 wk. The interval between splen- ectomy and r-aINF was at least 2 wk.

The r-aINF used in this study was recombinant- 2b-interferon, issued by Schering Corporation, in ampoules of 3 x lo6 units or 5 x lo6 units of lyophil- izate, with a specific activity of 2 x 10' IU/mg. The study protocol for induction therapy has been pre- viously described (10). Induction therapy consisted of r-a-INF for 16 wk by subcutaneous injection at an initial dose of 3 x lo6 U/d, with two scheduled monthly increments in cases of response failure. Increasing doses were: 5 x lo6 U/d and 10 x lo6 U/d.

For maintenance therapy, r-aINF dosage was individually adjusted according to the patient's he- matologic values. The aim of the long-term therapy was to find the minimum dose of the drug that maintained a platelet count lower than 500 x 109/1 and a WBC count lower than 20 x 109/l. In 1 case, hydroxyurea was associated to r-aINF for 4 wk with the aim of assessing the value of the combi- nation therapy. In 1 other case, hydroxyurea was alternatively administered for 4 wk with the aim of gaining a measure of the equivalent dose.

Results

Induction therapy. In all cases the induction therapy produced a definite decrease in platelet count from a mean of 845 x 109/1, range 215-1748, to a mean of 370 x 109/1, range 96-730, (p = 0.005). A definite WBC decrease (greater than 25% of the initial value) was actually observed in only 6 out of the 12 patients. WBC decreased from a mean of 43 x 109/1, range 6.4-69.4, to a mean of 16 x 109/1, range 5.0-39, (p = 0.05). r-aIFN did not produce signifi- cant changes in Hb values. In fact, Hb changed from a mean value of 13.04 g/dl, range 8.3-17.3, to a mean value of 12.1 g/dl, range 7.7.-18, (p> 0.05). Only 2 splenectomized patients responded at the starting dose of 3 x lo6 U/d. In the remaining

Maintenance therapy. r-aIFN therapy was pursued after induction therapy in 3 out of the 12 patients (2 males and 1 female). Their ages were, respec- tively, 64, 45 and 48 yr. They are actually under treatment at 10, 24 and 34 months. The aim of long-term therapy was of maintaining platelet count lower than 500 x 109/l. They entered main- tenance therapy with a platelet count of 435 x 109/1, 280 x 109/1 and 450 x 109/1, respectively. Their WBC was constantly lower than 20 x 109/1 and their Hb higher than 12 g/dl. 2 of the patients had been previously splenectomized and the 3rd had reached the disappearance of splenomegaly after induction therapy.

In all the patients, a low platelet count was main- tained with a dose of 10 MU/wk. When the dose was reduced to 6 MU/wk (case n. 3), platelet count increased over 500 x 109/1, so that the previous dose was restarted. Hydroxyurca, 1 g/die, when substi- tuted for r-a-INF, did not attain the same effect after 4 wk as did r-aINF, 10 MU/wk, so r-a-INF therapy was restarted (case 1). Hydroxyurca, 500 mg/die, when associated to r-a-INF, 6 MU/wk, proved to be effective in maintaining a low platelet count (case n. 2). In all the patients, during main- tenance therapy their WBC and Hb values re- mained close to their initial values.

The patients generally tolerated the therapy well, with relatively few side-effects, the most common of which were occasional episodes of mild to mod- erate fever. No marked changes occurred in the serum chemistry profiles. We observed no evidence of organ dysfunction that could be attributed to the therapy.

Discussion

We elected to treat patients with MMM with r- aINF only when in a hyperproliferative phase. They all had a hypercellular bone marrow, a WBC or platelet count above normal values.

The results of induction therapy in this series of 12 cases confirm what we obtained in a subset of the cases (10). The 16-wk treatment had a major beneficial effect in reducing the circulating platelet count. This result is consistent with the INF-in- duced reduction of platelet count reported in pa- tients with essential thrombocythemia (1 l ) and ex-

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Barosi et al.

cessive thrombocytosis in myeloproliferative dis- ease (12-15).

An assessment of the r-aINF maintenance dose after normalization of platelet count was per- formed in 3 out of the 12 patients. They received r-aINF from 10 to 34 months. A dose of 10 MU/ wk seems necessary to maintain the platelet count at the desired value, i.e. below 500 x 109/l. Minor modifications were observed, with this dose, in WBC and Hb values. A reduction of the dose resulted in 1 case in a relapse of thrombocytosis. 10 MU/wk of r-aINF seemed to be more effective than 1 g hydroxyurea/die in another case. This maintenance dose could be reduced to 6 MU/wk when associated to 500 mg hydroxyurea/die, as demonstrated in 1 other case.

All 3 patients who were submitted to long-term therapy tolerated the treatment with acceptable side-effects.

Long-term r-aINF therapy seems to be a clin- ically feasible and effective treatment for patients with MMM in which the main problem is a throm- bocytosis. A more consistent cost-effectiveness evaluation with respect to traditional cytostatic agents seems to be necessary for a more rational indication of this therapy.

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