Interferon Alfa-2a as Compared with Conventional Chemotherapy for the Treatment of Chronic Myeloid Leukemia

Patients

Table 1. Table 1. Clinical Characteristics of Patients with CML Treated with Interferon Alfa-2a or Conventional Chemotherapy (Hydroxyurea or Busulfan).

Between July 1986 and July 1988, 332 patients with Philadelphia chromosome (Ph¹)-positive CML were recruited, representing about 25 percent of the estimated number of patients with this disease in Italy over a two-year period¹¹. Ten patients did not meet the criteria for inclusion. The remaining 322 patients were randomly assigned to treatment as soon as they were found to be eligible: at each study center, two patients were assigned to interferon for each patient assigned to conventional chemotherapy. Their main clinical and hematologic features (218 patients in the interferon group and 104 in the chemotherapy group) are shown in Table 1.

Patients were eligible if they had Ph¹-positive CML in first chronic phase, their disease had been diagnosed within the preceding six months, and they had received only minimal treatment (<100 mg of busulfan or <50 g of hydroxyurea) or none. Patients were excluded if they were more than 70 years old, their disease was in an accelerated or a blastic phase, or they had any associated disorder that could markedly influence the evaluation of treatment or its toxicity. Patients gave consent orally or in writing, depending on the rules of the local ethics committee. Before they gave consent, the results of conventional chemotherapy^1-5 and the available information on interferon alfa^6,7 were described to them and their primary physicians. It was explained that treatment would be adjusted according to its side effects and their tolerance of it and that it would be discontinued at any time at the patient's request. The experimental nature of the trial and the need for more frequent clinical and laboratory evaluations than are usually required, including bone marrow studies, performed at no extra charge, were pointed out.

Treatment

Treatment was continued according to the study protocol unless the CML progressed to an accelerated or a blastic phase. On disease progression, the choice of treatment was left to the discretion of the investigator.

All 218 patients in the interferon group were given human recombinant interferon alfa-2a (Roferon-A, Hoffmann-LaRoche) at a daily dose of 3 million IU for the first two weeks, 6 million IU for another two weeks, and 9 million IU thereafter. After eight months of treatment, the dose was escalated according to the level of the karyotypic response (defined below): it was increased by 25 percent in patients with a minimal, minor, or major response, and by 50 percent in patients with no response. After the 14th month of treatment, the dose was kept the same in patients with any karyotypic response but was reduced to 3 million IU given three times a week in patients with no response. Treatment was adjusted for toxicity according to the following guidelines: for a grade II toxic reaction (as defined by the World Health Organization), the dose was reduced by 50 percent until recovery; for a grade III reaction, treatment was discontinued until recovery and then resumed at 50 percent of the previous dose; and for a grade IV (life-threatening) reaction, treatment was stopped if the reaction was nonhematologic, or was discontinued and then resumed at 50 percent of the previous dose if the reaction was hematologic. The protocol allowed chemotherapy to be added to treatment after 3 months if there was no hematologic response, after 8 months if there was poor hematologic control (a white-cell count >30,000 per cubic millimeter, a platelet count >750,000 per cubic millimeter, or a spleen palpable >5 cm below the left costal margin), and after 14 months if there was no karyotypic response.

The 104 patients in the conventional-chemotherapy group were given hydroxyurea as the first-line drug; busulfan was substituted for hydroxyurea in 10 of these patients (10 percent). The treatment dose and schedule were determined by the investigator; chemotherapy was mandatory if the white-cell count was more than 30,000 per cubic millimeter, the platelet count was more than 750,000 per cubic millimeter, or the spleen could be palpated more than 5 cm below the left costal margin.

The study protocol allowed any patient to undergo allogeneic bone marrow transplantation at any time.

Definition of Disease Progression and Response to Treatment

For the purpose of this study, the accelerated and blastic phases of leukemia were considered together. These phases were indicated by at least two of the following five predetermined criteria: a peripheral-blood sample containing more than 10 percent blast cells or more than 30 percent blast cells and promyelocytes; a bone marrow aspirate containing more than 15 percent blast cells or more than 50 percent blast cells and promyelocytes; a spleen that could be palpated more than 10 cm below the left costal margin and a white-cell count of less than 25,000 per cubic millimeter; involvement of the central nervous system, bone, lymph nodes, or other extrahematologic sites; and karyotypic evaluation revealing trisomy Ph¹, trisomy 8, or isochromosome 17.

The patients were stratified according to their risk of disease progression, with use of the formula proposed by Sokal et al.¹²; this formula is based on the patient's age, spleen size, platelet count, and percentage of blast cells in peripheral blood. Patients were considered at low risk if the relative risk was less than 0.8, at intermediate risk if the relative risk was 0.8 to 1.2, and at high risk if the relative risk was more than 1.2.

A hematologic response was defined as complete if all the following criteria were met: the hemoglobin concentration was more than 110 g per liter, the platelet count was less than 500,000 per cubic millimeter, the white-cell count was less than 10,000 per cubic millimeter, the differential blood count was normal, and the spleen could not be palpated. A response was defined as partial if any of the following findings were made: the hemoglobin concentration was 90 to 110 g per liter, the platelet count was 500,000 per cubic millimeter or higher, the white-cell count ranged from 10,000 to 50,000 per cubic millimeter, the differential blood count showed 1 to 5 percent precursor cells, or the spleen could be palpated 1 to 5 cm below the left costal margin.

A karyotypic response was defined according to the percentage of Ph¹-negative metaphases: responses were categorized as absent (0 percent), minimal (1 to 32 percent), minor (33 to 66 percent), major (67 to 99 percent), and complete (100 percent). The protocol required that at least 25 metaphases be examined to determine the karyotypic response, but responses determined by examination of 10 to 24 metaphases were also considered. A karyotype study (bone marrow cells) was required before treatment, at 8 and 14 months, and yearly thereafter.

Statistical Analysis

All patients were observed from randomization to April 30, 1993. By that date, 36 of the 322 patients (11 percent) had undergone allogeneic bone marrow transplantation while in their first chronic phase of leukemia (27 of 218 patients given interferon alfa-2a and 9 of 104 given conventional chemotherapy). Of the remaining 286 patients, 150 (52 percent) were dead and 136 were alive after a median follow-up of 68 months (range, 56 to 82). Survival and the time to progression to an accelerated or a blastic phase were calculated from the time of randomization to death, the date of disease progression, or the date of the last follow-up evaluation, according to the method of Kaplan and Meier¹³. Data on the patients who underwent transplantation while in first chronic phase were censored as of the date of transplantation. In the calculation of the time to disease progression, data on the patients who died while in first chronic phase or in an unidentified phase were censored as of the date of death.

All comparisons were based on the intention-to-treat principle and thus included all 322 patients regardless of the type or time of any protocol violation. An analysis of results in the interferon group alone excluded the patients who underwent transplantation (2 patients) or refused treatment (10 patients) during the first eight months of treatment.

Comparisons were made by the log-rank method,¹⁴ the chi-square test, and Student's t-test; P values are two-sided. Comparisons of subgroups of the interferon group also used logistic regression¹⁵ and Cox's proportional-hazard model for covariate analysis of censored data on survival¹⁶.

The number of patients studied was set so that the trial would have an 80 percent probability of detecting a 20 percent difference in median survival between a group given control treatment (the patients given conventional chemotherapy) and a group given the treatment of interest (the patients given interferon), on the assumptions that the median survival in the control group would be 48 months and that 10 percent of each group would be lost to observation each year.

Hematologic and Karyotypic Response

The proportion of hematologic responses (both complete and partial) was similar in the treatment groups after three months (45 percent in the interferon group and 46 percent in the conventional-chemotherapy group) and after eight months (62 and 53 percent, respectively); however, 78 patients in the interferon group (36 percent) were also given chemotherapy during that period. From the eighth month onward, 68 to 87 percent of all patients at risk (irrespective of treatment group) had a hematologic response.

Table 2. Table 2. Karyotypic Response.

The proportion and the degree of karyotypic responses varied over time, either because the true degree of response fluctuated or because data on karyotypes were occasionally missing. Therefore, for a better comparison, patients were grouped according to their best response (Table 2). Complete, major, and minor karyotypic responses were always more frequent in the interferon group than in the conventional-chemotherapy group, but the rate of minimal responses was nearly equal in the groups.

Survival and Disease Progression

Figure 1. Figure 1. Survival of Patients with CML Treated with Interferon Alfa-2a or Conventional Chemotherapy (Hydroxyurea or Busulfan).

All 322 patients randomly assigned to the treatments are represented, regardless of any protocol violation or the cause of death. Data on 36 patients who underwent allogeneic bone marrow transplantation in the first chronic phase were censored as of the date of transplantation. (The P value was determined by the log-rank test.).

The median survival of all 218 patients in the interferon group was reached at six years. The median survival of all 104 patients in the conventional-chemotherapy group was 52 months, and their 6-year survival was 29 percent (95 percent confidence interval, 17 to 41 percent) (Figure 1). These differences were significant (P = 0.002). When patients were stratified according to risk group, the median survival of those at low or intermediate risk was notably longer if they had been given interferon alfa-2a than if they had been given conventional chemotherapy (>72 vs. 64 months, P = 0.05); the median survival of patients at high risk was significantly longer if they had been given interferon (54 vs. 38 months, P = 0.01). All deaths occurred during an accelerated or a blastic phase, with the exception of 12 patients (8 given interferon and 4 given conventional chemotherapy) who died during first chronic phase and 3 patients whose disease phase at death could not be identified.

Figure 2. Figure 2. Rate of Disease Progression to an Accelerated or a Blastic Phase, According to Treatment Group.

All 322 patients were represented, regardless of any protocol violation. Data on 36 patients who underwent allogeneic bone marrow transplantation in the first chronic phase were censored as of the date of transplantation; data on 12 patients who died in the first chronic phase and 3 who died in an undefined phase were censored as of the date of death. (The P value was determined by the log-rank test.).

The cumulative rate of progression from the chronic phase to an accelerated or a blastic phase is shown in Figure 2. The median time to disease progression was more than 72 months in the interferon group and 45 months in the chemotherapy group (P<0.001).

Discontinuation and Adjustment of Treatment

Table 3. Table 3. Reasons for Stopping Treatment Assigned at Randomization.

The main reasons for stopping treatment are listed in Table 3. The treatment groups were balanced with respect to these reasons except for toxic reactions and side effects, which led 16 percent of the patients given interferon alfa-2a to stop treatment, as compared with none of those given conventional chemotherapy. Five years after randomization the cumulative proportion of patients who discontinued their assigned treatment was about 50 percent in the interferon group and 30 percent in the chemotherapy group (P = 0.04).

During the first 14 months, hydroxyurea was substituted for interferon alfa-2a in 23 patients (11 percent) (in 8 patients because they refused to continue interferon treatment, in 7 because interferon treatment was stopped, and in 8 in preparation for bone marrow transplantation). Hydroxyurea was added to interferon treatment in 66 patients (30 percent), with the aim of improving or accelerating their hematologic response. When these 89 patients were compared with the 129 given interferon alfa-2a only, their rate of karyotypic response was lower (13 percent vs. 40 percent) and their median survival shorter (48 vs. >72 months). The dose of interferon alfa-2a actually given was 76 to 100 percent of that scheduled for 53 percent of the patients, 50 to 75 percent of that scheduled for 29 percent, and less than 50 percent of that scheduled for 18 percent. The median dose was 4.28 million IU per square meter of body-surface area per day.

Toxicity and Side Effects

Two deaths during the chronic phase of CML could be attributed to treatment. A 45-year-old woman in the interferon group died suddenly at home, with anemia, leukopenia, and thrombocytopenia, after two months of treatment. A 57-year-old woman in the conventional-chemotherapy group died of pneumonitis with persistent leukopenia after 11 months of treatment with hydroxyurea (total, 120 g) and busulfan (total, 380 mg).

Table 4. Table 4. Toxicity and Side Effects in the Interferon Group.

Side effects were more frequent in the interferon group (Table 4) than in the conventional-chemotherapy group, in which grade I and II toxic reactions occurred in less than 10 percent of the patients and grade III and IV reactions in less than 4 percent (data not shown). Side effects were usually multiple -- for example, an influenza-like syndrome (asthenia, fever, myalgia, arthralgia, and headache) and nausea, anorexia, diarrhea, and weight loss. The main complication stopping treatment was polyneuropathy in three patients and a syndrome of confusion, dizziness, drowsiness, and depression in six others. A patient given 9 million IU of interferon alfa-2a daily (equal to 4.6 million IU per square meter) became comatose after eight months. When treatment was stopped in any patient with side effects, all neurologic complications cleared rapidly.

Findings in the Interferon Group

Time and Duration of Karyotypic Response

Table 5. Table 5. Distribution of Best Karyotypic Responses in the Interferon Group, According to the Time When the Best Response Was First Detected.

Of the 66 patients with a complete, major, or minor karyotypic response, 46 (70 percent) had some degree of response by 8 months, 14 (21 percent) by 14 months, and the remaining 6 (9 percent) by 24 months. However, the time that was necessary to achieve the best response was remarkably longer, and in several patients the first complete or major response was not detected until after several years of treatment (Table 5).

Among the 63 patients responding to treatment for whom follow-up data on karyotypic response were adequate, response was maintained or improved in 41 patients but disappeared in 22. At the most recent follow-up, the survival in these two subgroups was essentially the same (of the 22 patients with loss of response, 5 died in blastic phase, and of the 41 with continuing responses, 3 died in a blastic phase and 2 in the chronic phase).

Factors Associated with Response and Survival

Multivariate logistic-regression analysis showed that the disease-related variables that were significantly related to a better karyotypic response were a lower platelet count (P = 0.02) and a lower percentage of blast cells in peripheral blood (P = 0.009). The patient's age, spleen size, and risk group were not significantly related to response. A Cox proportional-hazards model demonstrated that the features that significantly lengthened survival were a higher hemoglobin concentration (P = 0.01), a lower percentage of blast cells in peripheral blood (P = 0.02), and a lower platelet count (P = 0.02). All these factors were not as significantly related to survival as was the patient's risk group (P = 0.001).

Figure 3. Figure 3. Survival in the Interferon Group from the Eighth Month Onward, According to the Degree of Hematologic Response after Eight Months of Treatment.

The 177 patients who were alive and in the chronic phase after eight months are represented. (The P value was determined by the log-rank test.).

To evaluate the relation of hematologic response at eight months to karyotypic response and survival, we restricted the analysis to the 177 patients who were alive and in the chronic phase after eight months of treatment. A karyotypic response occurred in 58 of 117 patients with hematologic responses, but in only 9 of 60 patients with no hematologic response (50 percent vs. 15 percent; P<0.001 by chi-square statistic; P = 0.002 by multivariate logistic regression). Survival was longer in the patients with hematologic responses than in those with no response (Figure 3).

Figure 4. Figure 4. Survival in the Interferon Group from the 24th Month Onward, According to the Best Karyotypic Response during the First 24 Months of Treatment.

The 140 patients who were alive and in the chronic phase after 24 months are represented. A response was categorized as complete, major, or minor if the percentage of Ph¹-negative metaphases was 33 percent or higher; a minimal response or a lack of response was indicated by a percentage of less than 33 percent. (The P value was determined by the log-rank test.).

To evaluate the relation of karyotypic response (complete, major, or minor) to survival, the analysis was restricted to the 140 patients who were alive and in the chronic phase after 24 months of treatment. Survival was longer in the patients with karyotypic responses than in those with no response (Figure 4). In these 140 patients, a Cox multivariate model showed that karyotypic response was more strongly related to survival than risk group (P<0.001 vs. P = 0.02).

After interferon alfa was shown to be therapeutically active against CML and to induce karyotypic remissions,^5-9,17,18 it remained to be established whether its use could modify the course of the disease and could prolong survival. To answer that question, we designed a prospective, multicenter trial comparing interferon alfa-2a with a standard treatment¹⁰. Previous trials of unconventional treatment of CML, including polychemotherapy, bone marrow transplantation, and interferon, had been uncontrolled, and their conclusions raised uncertainty and criticism.

An interim analysis of this trial¹⁹ showed that during the first two years, interferon was superior to hydroxyurea in inducing karyotypic responses. These results were confirmed in our study, especially in regard to patients with a complete or nearly complete karyotypic response.

Although the median survival of patients given conventional chemotherapy was longer (52 months) than that expected from study of historical series of patients,^1-5 the overall survival of the patients given interferon alfa-2a was significantly better, largely because of slowing of the progression of leukemia from the chronic phase to an accelerated or a blastic phase (Figure 2). These data confirm the findings of Talpaz et al.,¹⁸ who treated 96 patients with interferon alfa and reported a median survival of 62 months.

Since interferon treatment is time consuming and expensive, involves daily injections, and may have unpleasant side effects, it is important to identify the features that might help to predict response and survival. We found that a karyotypic response (complete, major, or minor) occurred more often in patients who had a normal platelet count and very few or no detectable blast cells in peripheral blood, and in the patients who had a hematologic response after less than eight months of interferon treatment.

This study did not address the relation of the dose of interferon alfa-2a to the response, the maintenance of response, or survival. The mean daily dose was initially the same, irrespective of the karyotypic response (4.11 million IU per square meter in the patients with no response vs. 4.45 million IU per square meter in those with responses). After 14 months, all patients with karyotypic responses continued to receive the maximal tolerated dose, but patients without a karyotypic response were given only 3 million IU three times a week. We do not know whether the patients with responses would have had a different outcome if they had received different maintenance doses, or whether the patients with no response would have eventually had a response if they had continued to receive the maximal tolerated dose. These points are probably important to the quality of life and the cost of treatment, which was 200 times higher for interferon alfa-2a than for hydroxyurea¹⁹.

When this trial was initiated, information about the use of interferon alfa for CML was very limited and more than half the study centers had no prior experience with this agent. Because of these facts, the multicenter nature of the study, and the inclusion of all patients in analyses according to the intention-to-treat principle, it is possible that our findings underestimate the efficacy of interferon against CML. They should therefore not be taken as a demonstration of the maximal possible efficacy of the agents tested, but they do suggest that the first-line drug selected for the treatment of CML should be interferon alfa.

The following are active members of the Italian Cooperative Study Group on Chronic Myeloid Leukemia: N. Testoni, M.D. Zamagni, G. Martinelli, and A. Zaccaria -- University of Bologna; D. Damiani and M. Michieli -- University of Udine; D. Criscuolo, C. Fowst, and E.E. Holdener -- Hoffmann-LaRoche, Milan and Basel; G. Specchia and V. Liso -- University of Bari; E. Morra and C. Bernasconi -- University of Pavia; E. Montefusco, G. Alimena, and F. Mandelli -- Universita La Sapienza, Rome; P. Leoni and G. Danieli -- University of Ancona; A. Nosari and F. De Cataldo -- Ospedale Niguarda Ca-Granda, Milan; I. Majolino and F. Caronia -- Ospedale Cervello, Palermo; A.M. Liberati, F. Grignani, A. Tabilio, and M. Martelli -- University of Perugia; F. Paolino and L. Resegotti -- Ospedale Molinette, Turin; A. Di Tucci and G. Broccia -- Ospedale Oncologico Businco, Cagliari; F. Leoni and S. Ciolli -- University of Florence; L. Luciano and B. Rotoli -- University of Naples; R. Perricone and A. Cajozzo -- University of Palermo; A. Montuoro and A. De Laurenzi -- Ospedale San Camillo, Rome; E. Volpe -- Ospedale Avellino; A. D'Emilio and R. Battista -- Ospedale Vicenza; A Capucci and T. Izzi -- Ospedale Brescia; G.L. Scapoli and G.L. Castoldi -- University of Ferrara; M. Lombardo and G. Torlontano -- University of Chieti; R. Landolfi and G. Leone -- Universita Cattolica, Rome; C. Delfini and G. Sparaventi -- Ospedale Pesaro; F. Papineschi and G. Spremolla -- University of Pisa; M. Risso and A.M. Marmont -- Ospedale San Martino, Genoa; D. Dini and U. Di Prisco -- University of Modena; L. Mangoni and V. Rizzoli -- University of Parma; M. Girino and E. Ascari -- University of Pavia; C.A. Bodenizza and M. Carotenuto -- Casa Sollievo della Sofferenza, San Giovanni Rotondo; A. Di Francesco and D. Quaglino -- University of l'Aquila; S. Nardelli and F. Ciccone -- Ospedale Latina; E. Miraglia and R. De Biase -- Ospedale Nuovo Pellegrini, Naples; E. Gallo and A. Pileri -- University of Turin; A. Rambaldi and T. Barbui -- Ospedale Bergamo; S. Morandi and E. Bianchini -- Ospedale Cremona; C. De Rosa and R. Cimino -- Ospedale Cardarelli, Naples; F. Ronca and F. Nobile -- Ospedale Reggio Calabria; M. Cantonetti and G. Papa -- Universita Tor Vergata, Rome; A. Gallamini and F. Buffa -- Ospedale Cuneo; C. Musolino and G. Squadrito -- University of Messina; A. Capaldi and E. Giovannelli -- Ospedale Mauriziano Umberto I, Turin; G. Pinotti and A. Venco -- Ospedale Varese; V. Zagonel and A. Pinto -- Centro Regionale di Riferimento Oncologico, Aviano; I. Gentilini and P. Coser -- Ospedale Bolzano; P. Guglielmo and E. Cacciola -- University of Catania; and M. Pizzuti and F. Ricciuti -- Ospedale Potenza.