Background In view of studies showing that interferon alfa waseffective treatment for chronic myeloid leukemia and that itprolonged survival, we organized a prospective, controlled comparativestudy of this treatment.
Methods We compared recombinant interferon alfa-2a with conventionalchemotherapy (hydroxyurea or busulfan) in a trial designed tohave a power of 80 percent to detect a difference of 20 percentin median survival between the group given interferon and thegroup given conventional chemotherapy. Between 1986 and 1988,322 patients with previously untreated or minimally treatedPhiladelphia chromosome-positive chronic myeloid leukemia wererandomly assigned to treatment with either interferon alfa-2a(218 patients) or conventional chemotherapy (104 patients).
Results The rate of karyotypic response (defined as >33 percentof metaphases negative for the Philadelphia chromosome) was30 percent in the interferon group and 5 percent in the conventional-chemotherapygroup (P<0.001). The time to progression from the chronicphase of leukemia to an accelerated or a blastic phase was longerin the interferon group than in the conventional-chemotherapygroup (median, >72 vs. 45 months; P<0.001), as was survival(median, 72 vs. 52 months; 6-year survival, 50 percent vs. 29percent; P = 0.002 for both comparisons). There was one treatment-relateddeath in each group. Treatment was discontinued because of sideeffects (mainly influenza-like, gastrointestinal, or neurologicsymptoms) in 35 patients given interferon alfa-2a (16 percent).The cost of interferon treatment was 200 times that of the conventionaltreatment.
Conclusions During long-term treatment of Philadelphia chromosome-positivechronic myeloid leukemia, interferon alfa-2a induced more karyotypicresponses than conventional chemotherapy, delayed disease progressionlonger, and prolonged overall survival more.
Chronic myeloid leukemia (CML) was treated for many years withradiation and with chemotherapy, mainly busulfan and hydroxyurea.Since that treatment neither prevented progression of the diseasefrom a chronic to a blastic phase nor substantially prolongedsurvival, other treatments were tested, including splenectomy,more aggressive chemotherapy similar to treatment that mightbe used for acute leukemia with or without autologous stem-cellrescue, and allogeneic bone marrow transplantation (these treatmentsare reviewed elsewhere1,2,3,4,5). Although these approacheswere not compared with conventional treatment, the results suggestedthat only transplantation prolonged survival and resulted incures, but bone marrow transplantation could be used only ina small proportion of cases. On the other hand, reports thatinterferon alfa could induce not only hematologic responsesbut also karyotypic remissions6,7,8,9 raised the question whetherthis agent could influence the course of the disease and theduration of survival. To answer this question, the Italian CooperativeStudy Group on Chronic Myeloid Leukemia undertook a prospectivetrial comparing interferon alfa with conventional chemotherapy10.
Methods
Patients
Between July 1986 and July 1988, 332 patients with Philadelphiachromosome (Ph1)-positive CML were recruited, representing about25 percent of the estimated number of patients with this diseasein Italy over a two-year period11. Ten patients did not meetthe criteria for inclusion. The remaining 322 patients wererandomly assigned to treatment as soon as they were found tobe eligible: at each study center, two patients were assignedto interferon for each patient assigned to conventional chemotherapy.Their main clinical and hematologic features (218 patients inthe interferon group and 104 in the chemotherapy group) areshown in Table 1.
Table 1. Clinical Characteristics of Patients with CML Treated with Interferon Alfa-2a or Conventional Chemotherapy (Hydroxyurea or Busulfan).
Patients were eligible if they had Ph1-positive CML in firstchronic phase, their disease had been diagnosed within the precedingsix months, and they had received only minimal treatment (<100mg of busulfan or <50 g of hydroxyurea) or none. Patientswere excluded if they were more than 70 years old, their diseasewas in an accelerated or a blastic phase, or they had any associateddisorder that could markedly influence the evaluation of treatmentor its toxicity. Patients gave consent orally or in writing,depending on the rules of the local ethics committee. Beforethey gave consent, the results of conventional chemotherapy1,2,3,4,5and the available information on interferon alfa6,7 were describedto them and their primary physicians. It was explained thattreatment would be adjusted according to its side effects andtheir tolerance of it and that it would be discontinued at anytime at the patient's request. The experimental nature of thetrial and the need for more frequent clinical and laboratoryevaluations than are usually required, including bone marrowstudies, performed at no extra charge, were pointed out.
Treatment
Treatment was continued according to the study protocol unlessthe CML progressed to an accelerated or a blastic phase. Ondisease progression, the choice of treatment was left to thediscretion of the investigator.
All 218 patients in the interferon group were given human recombinantinterferon alfa-2a (Roferon-A, Hoffmann-LaRoche) at a dailydose of 3 million IU for the first two weeks, 6 million IU foranother two weeks, and 9 million IU thereafter. After eightmonths of treatment, the dose was escalated according to thelevel of the karyotypic response (defined below): it was increasedby 25 percent in patients with a minimal, minor, or major response,and by 50 percent in patients with no response. After the 14thmonth of treatment, the dose was kept the same in patients withany karyotypic response but was reduced to 3 million IU giventhree times a week in patients with no response. Treatment wasadjusted for toxicity according to the following guidelines:for a grade II toxic reaction (as defined by the World HealthOrganization), the dose was reduced by 50 percent until recovery;for a grade III reaction, treatment was discontinued until recoveryand then resumed at 50 percent of the previous dose; and fora grade IV (life-threatening) reaction, treatment was stoppedif the reaction was nonhematologic, or was discontinued andthen resumed at 50 percent of the previous dose if the reactionwas hematologic. The protocol allowed chemotherapy to be addedto treatment after 3 months if there was no hematologic response,after 8 months if there was poor hematologic control (a white-cellcount >30,000 per cubic millimeter, a platelet count >750,000per cubic millimeter, or a spleen palpable >5 cm below theleft costal margin), and after 14 months if there was no karyotypicresponse.
The 104 patients in the conventional-chemotherapy group weregiven hydroxyurea as the first-line drug; busulfan was substitutedfor hydroxyurea in 10 of these patients (10 percent). The treatmentdose and schedule were determined by the investigator; chemotherapywas mandatory if the white-cell count was more than 30,000 percubic millimeter, the platelet count was more than 750,000 percubic millimeter, or the spleen could be palpated more than5 cm below the left costal margin.
The study protocol allowed any patient to undergo allogeneicbone marrow transplantation at any time.
Definition of Disease Progression and Response to Treatment
For the purpose of this study, the accelerated and blastic phasesof leukemia were considered together. These phases were indicatedby at least two of the following five predetermined criteria:a peripheral-blood sample containing more than 10 percent blastcells or more than 30 percent blast cells and promyelocytes;a bone marrow aspirate containing more than 15 percent blastcells or more than 50 percent blast cells and promyelocytes;a spleen that could be palpated more than 10 cm below the leftcostal margin and a white-cell count of less than 25,000 percubic millimeter; involvement of the central nervous system,bone, lymph nodes, or other extrahematologic sites; and karyotypicevaluation revealing trisomy Ph1, trisomy 8, or isochromosome17.
The patients were stratified according to their risk of diseaseprogression, with use of the formula proposed by Sokal et al.12;this formula is based on the patient's age, spleen size, plateletcount, and percentage of blast cells in peripheral blood. Patientswere considered at low risk if the relative risk was less than0.8, 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 followingcriteria were met: the hemoglobin concentration was more than110 g per liter, the platelet count was less than 500,000 percubic millimeter, the white-cell count was less than 10,000per cubic millimeter, the differential blood count was normal,and the spleen could not be palpated. A response was definedas partial if any of the following findings were made: the hemoglobinconcentration was 90 to 110 g per liter, the platelet countwas 500,000 per cubic millimeter or higher, the white-cell countranged from 10,000 to 50,000 per cubic millimeter, the differentialblood count showed 1 to 5 percent precursor cells, or the spleencould be palpated 1 to 5 cm below the left costal margin.
A karyotypic response was defined according to the percentageof 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 protocolrequired that at least 25 metaphases be examined to determinethe karyotypic response, but responses determined by examinationof 10 to 24 metaphases were also considered. A karyotype study(bone marrow cells) was required before treatment, at 8 and14 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 undergoneallogeneic bone marrow transplantation while in their firstchronic phase of leukemia (27 of 218 patients given interferonalfa-2a and 9 of 104 given conventional chemotherapy). Of theremaining 286 patients, 150 (52 percent) were dead and 136 werealive after a median follow-up of 68 months (range, 56 to 82).Survival and the time to progression to an accelerated or ablastic phase were calculated from the time of randomizationto death, the date of disease progression, or the date of thelast follow-up evaluation, according to the method of Kaplanand Meier13. Data on the patients who underwent transplantationwhile in first chronic phase were censored as of the date oftransplantation. In the calculation of the time to disease progression,data on the patients who died while in first chronic phase orin an unidentified phase were censored as of the date of death.
All comparisons were based on the intention-to-treat principleand thus included all 322 patients regardless of the type ortime of any protocol violation. An analysis of results in theinterferon group alone excluded the patients who underwent transplantation(2 patients) or refused treatment (10 patients) during the firsteight months of treatment.
Comparisons were made by the log-rank method,14 the chi-squaretest, and Student's t-test; P values are two-sided. Comparisonsof subgroups of the interferon group also used logistic regression15and Cox's proportional-hazard model for covariate analysis ofcensored data on survival16.
The number of patients studied was set so that the trial wouldhave an 80 percent probability of detecting a 20 percent differencein median survival between a group given control treatment (thepatients given conventional chemotherapy) and a group giventhe treatment of interest (the patients given interferon), onthe assumptions that the median survival in the control groupwould be 48 months and that 10 percent of each group would belost to observation each year.
Results
Hematologic and Karyotypic Response
The proportion of hematologic responses (both complete and partial)was similar in the treatment groups after three months (45 percentin the interferon group and 46 percent in the conventional-chemotherapygroup) and after eight months (62 and 53 percent, respectively);however, 78 patients in the interferon group (36 percent) werealso given chemotherapy during that period. From the eighthmonth onward, 68 to 87 percent of all patients at risk (irrespectiveof treatment group) had a hematologic response.
The proportion and the degree of karyotypic responses variedover time, either because the true degree of response fluctuatedor because data on karyotypes were occasionally missing. Therefore,for a better comparison, patients were grouped according totheir best response (Table 2). Complete, major, and minor karyotypicresponses were always more frequent in the interferon groupthan in the conventional-chemotherapy group, but the rate ofminimal responses was nearly equal in the groups.
The median survival of all 218 patients in the interferon groupwas reached at six years. The median survival of all 104 patientsin the conventional-chemotherapy group was 52 months, and their6-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 riskgroup, the median survival of those at low or intermediate riskwas notably longer if they had been given interferon alfa-2athan if they had been given conventional chemotherapy (>72vs. 64 months, P = 0.05); the median survival of patients athigh risk was significantly longer if they had been given interferon(54 vs. 38 months, P = 0.01). All deaths occurred during anaccelerated or a blastic phase, with the exception of 12 patients(8 given interferon and 4 given conventional chemotherapy) whodied during first chronic phase and 3 patients whose diseasephase at death could not be identified.
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 cumulative rate of progression from the chronic phase toan accelerated or a blastic phase is shown in Figure 2. Themedian time to disease progression was more than 72 months inthe interferon group and 45 months in the chemotherapy group(P<0.001).
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.).
Discontinuation and Adjustment of Treatment
The main reasons for stopping treatment are listed in Table 3.The treatment groups were balanced with respect to thesereasons except for toxic reactions and side effects, which led16 percent of the patients given interferon alfa-2a to stoptreatment, as compared with none of those given conventionalchemotherapy. Five years after randomization the cumulativeproportion of patients who discontinued their assigned treatmentwas about 50 percent in the interferon group and 30 percentin the chemotherapy group (P = 0.04).
Table 3. Reasons for Stopping Treatment Assigned at Randomization.
During the first 14 months, hydroxyurea was substituted forinterferon alfa-2a in 23 patients (11 percent) (in 8 patientsbecause they refused to continue interferon treatment, in 7because interferon treatment was stopped, and in 8 in preparationfor bone marrow transplantation). Hydroxyurea was added to interferontreatment in 66 patients (30 percent), with the aim of improvingor accelerating their hematologic response. When these 89 patientswere compared with the 129 given interferon alfa-2a only, theirrate of karyotypic response was lower (13 percent vs. 40 percent)and their median survival shorter (48 vs. >72 months). Thedose of interferon alfa-2a actually given was 76 to 100 percentof that scheduled for 53 percent of the patients, 50 to 75 percentof that scheduled for 29 percent, and less than 50 percent ofthat scheduled for 18 percent. The median dose was 4.28 millionIU per square meter of body-surface area per day.
Toxicity and Side Effects
Two deaths during the chronic phase of CML could be attributedto treatment. A 45-year-old woman in the interferon group diedsuddenly at home, with anemia, leukopenia, and thrombocytopenia,after two months of treatment. A 57-year-old woman in the conventional-chemotherapygroup died of pneumonitis with persistent leukopenia after 11months of treatment with hydroxyurea (total, 120 g) and busulfan(total, 380 mg).
Side effects were more frequent in the interferon group (Table 4)than in the conventional-chemotherapy group, in which gradeI and II toxic reactions occurred in less than 10 percent ofthe patients and grade III and IV reactions in less than 4 percent(data not shown). Side effects were usually multiple -- forexample, an influenza-like syndrome (asthenia, fever, myalgia,arthralgia, and headache) and nausea, anorexia, diarrhea, andweight loss. The main complication stopping treatment was polyneuropathyin three patients and a syndrome of confusion, dizziness, drowsiness,and depression in six others. A patient given 9 million IU ofinterferon alfa-2a daily (equal to 4.6 million IU per squaremeter) became comatose after eight months. When treatment wasstopped in any patient with side effects, all neurologic complicationscleared rapidly.
Table 4. Toxicity and Side Effects in the Interferon Group.
Findings in the Interferon Group
Time and Duration of Karyotypic Response
Of the 66 patients with a complete, major, or minor karyotypicresponse, 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 achievethe best response was remarkably longer, and in several patientsthe first complete or major response was not detected untilafter several years of treatment (Table 5).
Table 5. Distribution of Best Karyotypic Responses in the Interferon Group, According to the Time When the Best Response Was First Detected.
Among the 63 patients responding to treatment for whom follow-updata on karyotypic response were adequate, response was maintainedor improved in 41 patients but disappeared in 22. At the mostrecent follow-up, the survival in these two subgroups was essentiallythe same (of the 22 patients with loss of response, 5 died inblastic phase, and of the 41 with continuing responses, 3 diedin a blastic phase and 2 in the chronic phase).
Factors Associated with Response and Survival
Multivariate logistic-regression analysis showed that the disease-relatedvariables that were significantly related to a better karyotypicresponse were a lower platelet count (P = 0.02) and a lowerpercentage of blast cells in peripheral blood (P = 0.009). Thepatient's age, spleen size, and risk group were not significantlyrelated to response. A Cox proportional-hazards model demonstratedthat the features that significantly lengthened survival werea higher hemoglobin concentration (P = 0.01), a lower percentageof blast cells in peripheral blood (P = 0.02), and a lower plateletcount (P = 0.02). All these factors were not as significantlyrelated to survival as was the patient's risk group (P = 0.001).
To evaluate the relation of hematologic response at eight monthsto karyotypic response and survival, we restricted the analysisto the 177 patients who were alive and in the chronic phaseafter eight months of treatment. A karyotypic response occurredin 58 of 117 patients with hematologic responses, but in only9 of 60 patients with no hematologic response (50 percent vs.15 percent; P<0.001 by chi-square statistic; P = 0.002 bymultivariate logistic regression). Survival was longer in thepatients with hematologic responses than in those with no response(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 karyotypic response (complete, major,or minor) to survival, the analysis was restricted to the 140patients who were alive and in the chronic phase after 24 monthsof treatment. Survival was longer in the patients with karyotypicresponses than in those with no response (Figure 4). In these140 patients, a Cox multivariate model showed that karyotypicresponse was more strongly related to survival than risk group(P<0.001 vs. P = 0.02).
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.).
Discussion
After interferon alfa was shown to be therapeutically activeagainst CML and to induce karyotypic remissions,5,6,7,8,9,17,18it remained to be established whether its use could modify thecourse of the disease and could prolong survival. To answerthat question, we designed a prospective, multicenter trialcomparing interferon alfa-2a with a standard treatment10. Previoustrials 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 firsttwo years, interferon was superior to hydroxyurea in inducingkaryotypic responses. These results were confirmed in our study,especially in regard to patients with a complete or nearly completekaryotypic response.
Although the median survival of patients given conventionalchemotherapy was longer (52 months) than that expected fromstudy of historical series of patients,1,2,3,4,5 the overallsurvival of the patients given interferon alfa-2a was significantlybetter, largely because of slowing of the progression of leukemiafrom the chronic phase to an accelerated or a blastic phase(Figure 2). These data confirm the findings of Talpaz et al.,18who treated 96 patients with interferon alfa and reported amedian 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 topredict response and survival. We found that a karyotypic response(complete, major, or minor) occurred more often in patientswho had a normal platelet count and very few or no detectableblast cells in peripheral blood, and in the patients who hada hematologic response after less than eight months of interferontreatment.
This study did not address the relation of the dose of interferonalfa-2a to the response, the maintenance of response, or survival.The mean daily dose was initially the same, irrespective ofthe karyotypic response (4.11 million IU per square meter inthe patients with no response vs. 4.45 million IU per squaremeter in those with responses). After 14 months, all patientswith karyotypic responses continued to receive the maximal tolerateddose, but patients without a karyotypic response were givenonly 3 million IU three times a week. We do not know whetherthe patients with responses would have had a different outcomeif they had received different maintenance doses, or whetherthe patients with no response would have eventually had a responseif they had continued to receive the maximal tolerated dose.These points are probably important to the quality of life andthe cost of treatment, which was 200 times higher for interferonalfa-2a than for hydroxyurea19.
When this trial was initiated, information about the use ofinterferon alfa for CML was very limited and more than halfthe study centers had no prior experience with this agent. Becauseof these facts, the multicenter nature of the study, and theinclusion of all patients in analyses according to the intention-to-treatprinciple, it is possible that our findings underestimate theefficacy of interferon against CML. They should therefore notbe taken as a demonstration of the maximal possible efficacyof the agents tested, but they do suggest that the first-linedrug selected for the treatment of CML should be interferonalfa.
Supported by the National Research Council, Italy, by grants(92.02128.PF39 and 92.02280.PF39) from P.F. Applicazioni Clinichedella Ricerca Oncologica, and by the Italian Association forCancer Research, Milan.
Source Information
The Writing Committee of the Italian Cooperative Study on Chronic Myeloid Leukemia consisted of Sante Tura (Institute of Hematology "L. and A. Seragnoli," University of Bologna), Michele Baccarani (Chair of Hematology, University of Udine), Eliana Zuffa (Institute of Hematology "L. and A. Seragnoli," University of Bologna), Domenico Russo (Chair of Hematology, University of Udine), Renato Fanin (Chair of Hematology, University of Udine), Alfonso Zaccaria (Institute of Hematology "L. and A. Seragnoli," University of Bologna), and Mauro Fiacchini (Institute of Hematology "L. and A. Seragnoli," University of Bologna). Other members of the study group are listed in the Appendix.
Address reprint requests to Professor Michele Baccarani at the Division of Hematology, Udine University Hospital, 33100 Udine, Italy.
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Appendix
The following are active members of the Italian CooperativeStudy 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 andC. Bernasconi -- University of Pavia; E. Montefusco, G. Alimena,and F. Mandelli -- Universita La Sapienza, Rome; P. Leoni andG. 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. Paolinoand L. Resegotti -- Ospedale Molinette, Turin; A. Di Tucci andG. Broccia -- Ospedale Oncologico Businco, Cagliari; F. Leoniand S. Ciolli -- University of Florence; L. Luciano and B. Rotoli-- University of Naples; R. Perricone and A. Cajozzo -- Universityof 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. Landolfiand 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 -- OspedaleSan Martino, Genoa; D. Dini and U. Di Prisco -- University ofModena; L. Mangoni and V. Rizzoli -- University of Parma; M.Girino and E. Ascari -- University of Pavia; C.A. Bodenizzaand M. Carotenuto -- Casa Sollievo della Sofferenza, San GiovanniRotondo; A. Di Francesco and D. Quaglino -- University of l'Aquila;S. Nardelli and F. Ciccone -- Ospedale Latina; E. Miraglia andR. De Biase -- Ospedale Nuovo Pellegrini, Naples; E. Gallo andA. Pileri -- University of Turin; A. Rambaldi and T. Barbui-- Ospedale Bergamo; S. Morandi and E. Bianchini -- OspedaleCremona; C. De Rosa and R. Cimino -- Ospedale Cardarelli, Naples;F. Ronca and F. Nobile -- Ospedale Reggio Calabria; M. Cantonettiand G. Papa -- Universita Tor Vergata, Rome; A. Gallamini andF. Buffa -- Ospedale Cuneo; C. Musolino and G. Squadrito --University of Messina; A. Capaldi and E. Giovannelli -- OspedaleMauriziano Umberto I, Turin; G. Pinotti and A. Venco -- OspedaleVarese; V. Zagonel and A. Pinto -- Centro Regionale di RiferimentoOncologico, Aviano; I. Gentilini and P. Coser -- Ospedale Bolzano;P. Guglielmo and E. Cacciola -- University of Catania; and M.Pizzuti and F. Ricciuti -- Ospedale Potenza.
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Mollee, P., Arthur, C., Hughes, T., Januszewicz, H., Grigg, A., Bradstock, K., Wolf, M., Gibson, J., Schwarer, A. P., Spencer, A., Browett, P., Hawkins, T., Seldon, M., Herrmann, R., Watson, A., Seymour, J. F., Martin, N., Shina, S., Low, C., Wright, S., Rodwell, R., Coulston, J., Morton, J., Blacklock, H., Taylor, D., Taylor, K. M.
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(2004). Randomized comparison of low-dose versus high-dose interferon-alfa in chronic myeloid leukemia: prospective collaboration of 3 joint trials by the MRC and HOVON groups. Blood
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Stone, R. M.
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Kantarjian, H., Talpaz, M., O'Brien, S., Garcia-Manero, G., Verstovsek, S., Giles, F., Rios, M. B., Shan, J., Letvak, L., Thomas, D., Faderl, S., Ferrajoli, A., Cortes, J.
(2004). High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood
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DeAngelo, D. J., Ritz, J.
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Huntly, B. J. P., Guilhot, F., Reid, A. G., Vassiliou, G., Hennig, E., Franke, C., Byrne, J., Brizard, A., Niederwieser, D., Freeman-Edward, J., Cuthbert, G., Bown, N., Clark, R. E., Nacheva, E. P, Green, A. R, Deininger, M. W. N.
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Cortes, J., Giles, F., O'Brien, S., Thomas, D., Garcia-Manero, G., Rios, M. B., Faderl, S., Verstovsek, S., Ferrajoli, A., Freireich, E. J., Talpaz, M., Kantarjian, H.
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(2001). The effect of pretransplant interferon therapy on the outcome of unrelated donor hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia in first chronic phase. Blood
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(2001). Chronic myeloid leukemia and interferon-alpha : a study of complete cytogenetic responders. Blood
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Huntly, B. J. P., Reid, A. G., Bench, A. J., Campbell, L. J., Telford, N., Shepherd, P., Szer, J., Prince, H. M., Turner, P., Grace, C., Nacheva, E. P., Green, A. R.
(2001). Deletions of the derivative chromosome 9 occur at the time of the Philadelphia translocation and provide a powerful and independent prognostic indicator in chronic myeloid leukemia. Blood
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Kalidas, M., Kantarjian, H., Talpaz, M.
(2001). Chronic Myelogenous Leukemia. JAMA
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Kvasnicka, H. M., Thiele, J., Schmitt-Graeff, A., Diehl, V., Zankovich, R., Niederle, N., Leder, L.-D., Schaefer, H. E.
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Kano, Y., Akutsu, M., Tsunoda, S., Mano, H., Sato, Y., Honma, Y., Furukawa, Y.
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Kantarjian, H., Melo, J. V., Tura, S., Giralt, S., Talpaz, M.
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Silver, R. T., Woolf, S. H., Hehlmann, R., Appelbaum, F. R., Anderson, J., Bennett, C., Goldman, J. M., Guilhot, F., Kantarjian, H. M., Lichtin, A. E., Talpaz, M., Tura, S.
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Stagno, F., Guglielmo, P., Consoli, U., Fiumara, P., Russo, M., Giustolisi, R.
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