Background Treatment with interferon prolongs survival in chronicmyelogenous leukemia. We conducted a clinical trial to assessthe efficacy of treatment with a combination of interferon andcytarabine.
Methods Previously untreated patients with chronic myelogenousleukemia were randomly assigned to receive either hydroxyurea(50 mg per kilogram of body weight per day) and interferon alfa-2b(5 million units per square meter of body-surface area per day),or hydroxyurea and interferon in the same dosages plus monthlycourses of cytarabine (20 mg per square meter per day, for 10days). The end points were overall survival, complete hematologicremission at 6 months, and major cytogenetic response (lessthan 35 percent Philadelphia chromosome–positive cellsin the bone marrow) at 12 months.
Results The trial was stopped when a sequential analysis showeda benefit of interferon and cytarabine. A significant improvementin survival was observed in the interferon–cytarabinegroup (360 patients) as compared with the interferon group (361patients) (P = 0.02; relative risk of death, 0.64; 95 percentconfidence interval, 0.44 to 0.93). After three years, the survivalrate was 85.7 percent with interferon and cytarabine and 79.1percent with interferon alone. The rate of hematologic responsewas higher in the interferon–cytarabine group than inthe interferon group (P = 0.003). Major cytogenetic responseswere observed 12 months after randomization in 126 of 311 patientstreated with interferon and cytarabine (41 percent) and in 75of 314 patients treated with interferon only (24 percent, P<0.001).
Conclusions The combination of interferon and cytarabine, ascompared with interferon alone, increases the rate of majorcytogenetic response and prolongs survival in patients in thechronic phase of chronic myelogenous leukemia.
Chronic myelogenous leukemia has a poor outcome when treatedwith hydroxyurea or busulfan. These agents can control the disease,but they do not eliminate Philadelphia chromosome–positivestem cells from the bone marrow. Allogeneic bone marrow transplantation,considered to be the only curative treatment, prolongs survivalin up to 70 percent of a small subgroup of young patients.1An antileukemic effect of interferon alfa has been demonstratedand cytogenetic responses (the reduction or elimination of Philadelphiachromosome–positive cells in the marrow) have been reportedin patients with chronic myelogenous leukemia.2,3,4 Three randomizedclinical trials comparing interferon alfa with conventionalchemotherapy have shown a significant survival benefit amongpatients receiving interferon,5,6,7 but complete cytogeneticresponses were found in only 10 to 20 percent of patients. Cytarabinehas an antileukemic activity in vitro,8 and when given subcutaneously,it can reduce the number of Philadelphia chromosome–positivecells in the marrow.9,10 After a pilot study11 suggested anadditive effect of low-dose cytarabine and interferon, a multicenter,sequential, randomized trial was begun to compare interferonand cytarabine with interferon alone.
Methods
Patients
Patients with chronic myelogenous leukemia were eligible ifthey were under 70 years of age, had tested positive for thePhiladelphia chromosome, were in the chronic phase of the disease,had been given a diagnosis within the preceding six months,and had previously been treated only with hydroxyurea. Patientswith features of accelerated or blastic phases of chronic myelogenousleukemia were not eligible, nor were those with a history ofdepressive illness or another psychiatric disorder or severehepatic, renal, or cardiovascular disorders.12 All the patientsgave informed consent to participation in the study, which wasapproved by the institutional review board of the HôpitalSaint-Louis, Paris.
Study Design
Using Sokal's formula,13,14 we calculated a prognostic scorefor each patient based on the patient's sex, age, spleen size,platelet count, percentage of blast cells in peripheral blood,and hematocrit. Patients were considered at low risk if thescore was below 0.8, at intermediate risk if it was between0.8 and 1.2, and at high risk if the score was above 1.2. Ifa family member was available to be a donor, allogeneic bonemarrow transplantation was required for all patients under 35years of age regardless of their Sokal score, and also for high-riskpatients from 35 to 50 years of age. Stem-cell collection wasrecommended at diagnosis for patients under 60 years of age.Those without donors and the remaining eligible patients wereenrolled and randomly assigned to one of the two groups by theBiometric Center.
Hydroxyurea and interferon alfa-2b were given simultaneouslyto all patients as induction treatment. Hydroxyurea was givenat a daily dose of 50 mg per kilogram of body weight or less,depending on the patient's white-cell count. Hydroxyurea wasdiscontinued when a complete hematologic remission was achieved.Interferon alfa-2b was given subcutaneously at an initial doseof 5 million units per square meter of body-surface area, oncea day. The dose of interferon was reduced by half when the granulocytecount dropped below 1500 per cubic millimeter, the plateletcount dropped below 100,000 per cubic millimeter, or both; interferonwas discontinued when the granulocyte count fell below 1000per cubic millimeter, the platelet count below 50,000 per cubicmillimeter, or both.
The patients in the interferon–cytarabine group receivedthe same induction regimen and in addition, after 2 weeks, monthlycourses of subcutaneous cytarabine in a single daily dose of20 mg per square meter for 10 days. Each course of cytarabinewas begun if, at the time of the planned treatment, the white-cellcount was above 3000 per cubic millimeter and the platelet countabove 100,000 per cubic millimeter. Cytarabine was discontinuedif the granulocyte count dropped below 1000 per cubic millimeteror the platelet count dropped below 50,000 per cubic millimeter.If suitable hematologic control was not achieved, the totaldose of cytarabine could be increased to 40 mg per day for 15days each month. Cytarabine was discontinued if karyotypingon two consecutive occasions revealed a complete cytogeneticresponse. The administration of interferon was continued unlessthere were serious adverse effects as defined by the World HealthOrganization.15 Blood counts were performed weekly during thefirst month and every other week thereafter. Interferon andcytarabine were administered in the patients' homes by nurses.
Patients in complete hematologic remission after six monthscontinued to receive the assigned treatment. Patients in theinterferon group who did not have complete hematologic remissioncould receive cytarabine after six months. However, if a relateddonor was found, allogeneic bone marrow transplantation wasproposed if the patient's age and condition were appropriate.Patients receiving interferon and cytarabine who were not incomplete hematologic remission could discontinue the study treatmentor consider an allograft as soon as possible. An autologousreinfusion of unmanipulated stem cells could be performed afterhigh-dose chemotherapy if there was no suitable donor. Otherpatients who were not in remission after six months were givenstandard oral chemotherapy, mainly hydroxyurea. After 12 monthsof treatment, the same possibilities applied to patients whodid not have at least a partial cytogenetic response (thosewith >35 percent Philadelphia chromosome–positive cellsin metaphase).
End Points
The end points were overall survival, the presence of a hematologicresponse at 6 months, and the presence of a cytogenetic responseat 12 months. Hematologic responses were evaluated six monthsafter randomization. The criteria for a complete hematologicresponse were the absence of disease-related symptoms and splenicenlargement by physical examination, a white-cell count below10,000 per cubic millimeter and a normal differential count(the presence of 1 to 5 percent immature granulocytes was alsoacceptable), a platelet count below 350,000 per cubic millimeter,and no treatment with hydroxyurea. Cytogenetic responses weredetermined according to the percentage of Philadelphia chromosome–positivecells in metaphase. Karyotypic analysis was required after 6and 12 months of treatment and was optional at months 3 and9; after 12 months, it was required every 4 months. A completecytogenetic response was defined by the absence of detectablePhiladelphia chromosome–positive cells in metaphase; partialand minor cytogenetic responses were defined as decreases inthe proportion of such cells to 1 to 34 percent and 35 to 94percent, respectively; major responses included complete andpartial responses. During follow-up, a median of 30 metaphaseswere examined. A karyotype with less than 5 cells in metaphasewas discarded and had to be repeated. If there were fewer than10 cells in metaphase, the data were skipped unless the resultsfitted into a pattern observed on previous tests. The karyotypeswere analyzed by members of the Groupe Français de CytogénétiqueHématologique.
Statistical Analysis
The study was designed to have a type I error of 5 percent witha power of 90 percent for the detection of increased survival(82 percent vs. 72.5 percent) after three years due to treatmentwith interferon and cytarabine as compared with interferon alone.To minimize the sample size and obtain results more rapidly,we conducted the study as a sequential trial using the triangulartest.16 The accumulated data were examined after approximatelyevery 15 deaths. At each sequential analysis, the z and V statisticswere calculated. A positive z value indicated that interferonplus cytarabine was superior to interferon alone, and a negativevalue indicated that interferon plus cytarabine was inferior.The V statistic is related to the number of deaths. Once thesequential values of z and V were calculated, they were plotted,and the sample path was compared with the stopping boundaries.If the plotted point lay above the upper boundary (indicatingthat interferon plus cytarabine was more effective than interferonalone) or below the lower boundary, the trial had to be stopped.
The statistical analysis was performed on an intention-to-treatbasis, provided that the patients fulfilled the major criteriafor inclusion in the study. The study groups were compared bythe Wilcoxon test in the case of continuous variables, by Fisher'sexact test in the case of binary variables, and by the chi-squaretest in the case of categorical variables. Survival distributionswere estimated by the Kaplan–Meier method17 and comparedby the log-rank test.18 To determine the factors predictiveof death and adjust the comparison of treatments for the patients'base-line characteristics, we used a Cox model.19 All the testswere two-sided except the triangular test. Because it takestime to achieve a cytogenetic response, survival was measuredfrom a prespecified "landmark" time of one year after randomizationin a landmark analysis.20 The median duration of treatment andthe time to a hematologic response were analyzed with data onthe time to treatment failure. The analysis used SAS (SAS Institute,Cary, N.C.) and PEST (MPS, Reading, United Kingdom) software.
Results
From January 1991 to May 1996, 810 patients were enrolled inthe study. Randomization occurred immediately for 623 patientsand was delayed for 187 patients, for whom a search for a relateddonor was required. Among these 187 patients, 65 were referredfor allogeneic bone marrow transplantation; the other 122 patientswere subsequently randomized because of the lack of a relateddonor. Thus, a total of 745 patients were included in the study.
At the fifth sequential analysis of the study, performed in1996 with data as of July 1, 1995, 75 deaths were reported:26 in the interferon–cytarabine group and 49 in the interferongroup. Since with these data the sample path crossed the upperboundary of the continuation region, the study was ended andit was concluded that the combination of interferon and cytarabineincreases survival (P = 0.01).
The analysis reported here was performed with data as of July1, 1996, at which time one patient had been lost to follow-up.Among the 745 patients in the study, 12 in each group were excludedfor the following reasons: 6 in each group were Philadelphiachromosome–negative, although they each had evidence ofa BCR-ABL molecular rearrangement; 5 had evidence of other myeloproliferativedisorders; 3 declined immediately to participate in the study;and 4 did not fulfill the major criteria for inclusion. Thus,721 patients were studied: 360 had been randomly assigned tothe interferon–cytarabine group, and 361 to the interferongroup. The median period of follow-up was 35 months. There wereno imbalances between the two groups at the time of randomizationwith respect to the patients' main clinical and laboratory features,and the risk categories (low, intermediate, and high) determinedon the basis of the Sokal score were evenly distributed betweenthe groups (Table 1).
Table 1. Clinical and Biologic Characteristics of the Study Patients According to Treatment Assignment.
Hematologic and Cytogenetic Responses
The rate of complete hematologic response was higher in theinterferon–cytarabine group (237 of 360 patients, or 66percent) than in the interferon group (198 of 361 patients,or 55 percent; P = 0.003 by Fisher's exact test). For the interferongroup, the relative risk of a complete hematologic responsewas 0.83 (95 percent confidence interval, 0.74 to 0.94). However,the time needed to reach a complete response was similar inboth groups (three months).
As Table 2 shows, the proportion of patients with a major cytogeneticresponse was significantly higher in the interferon–cytarabinegroup than in the interferon group (P<0.001 by Fisher's exacttest). The relative risk of a major cytogenetic response inthe interferon group was 0.59 (95 percent confidence interval,0.46 to 0.75). In both groups, the degree of risk was significantlycorrelated with the occurrence of a major cytogenetic response:in the interferon–cytarabine group, 47 percent of patientsat low risk, 39 percent of those at intermediate risk, and 19percent of those at high risk had such responses (P = 0.006),as compared with 40, 13, and 12 percent, respectively, of thepatients in the interferon group (P = 0.001). The frequencyof major cytogenetic responses remained significantly higherwith interferon plus cytarabine after adjustment for Sokal'sindex (P = 0.001).
Table 2. Cytogenetic Responses at 12 Months, According to Treatment Assignment.
Among the 721 study patients, the probability of having a majorcytogenetic response at 24 months was estimated to be 54 percentin the interferon–cytarabine group and 41 percent in theinterferon group (P = 0.006; relative risk, 0.73; 95 percentconfidence interval, 0.59 to 0.91).
Survival and Prognostic Factors
The patients in the interferon–cytarabine group survivedsignificantly longer than those in the interferon group (P =0.02 by the log-rank test; relative risk of death, 0.64; 95percent confidence interval, 0.44 to 0.93). At three years theestimated survival rates were 85.7 percent in the interferon–cytarabinegroup and 79.1 percent in the interferon group (Figure 1). Thedifference in survival rates remained statistically significantwhen the data on patients who received allogeneic bone marrowtransplants were censored (P = 0.03), as well as when the dataon patients who received any type of transplant or who diedfor reasons unrelated to chronic myelogenous leukemia were censored(P = 0.02). Table 3 shows the causes of death; blastic transformationwas the predominant cause in each group. In the univariate analysis,five disease-related variables influenced survival significantly:spleen size, hematocrit, hemoglobin level, white-cell count,and presence of blast cells in blood. After stepwise backwardCox proportional-hazards analysis, only the hemoglobin levelremained significant (P = 0.005). After adjustment for disease-relatedvariables and the Sokal score, overall survival remained significantlyhigher in the interferon–cytarabine group (P = 0.03; relativerisk of death, 0.67; 95 percent confidence interval, 0.46 to0.97).
Table 3. Causes of Death in the Study Patients with Chronic Myelogenous Leukemia (CML), According to Treatment Assignment.
Effect of Cytogenetic Response on Survival
Survival rates were also analyzed according to cytogenetic responseby the landmark method. In the interferon–cytarabine group,patients who had a partial or complete cytogenetic responsesurvived longer (P<0.001) than patients with no responseor a minor response (Figure 2A). This difference was also significantin the interferon group (P<0.001) (Figure 2B).
Figure 2. Landmark Analysis of Survival at 12 Months in the Interferon–Cytarabine Group (Panel A) and the Interferon Group (Panel B), According to Cytogenetic Response.
All the patients remaining alive at 12 months were classified according to whether they had a major cytogenetic response as compared with a minor response or no response. Data were censored as of the date of transplantation for the patients who underwent transplantation and as of the date of death for the patients who died of causes other than chronic myelogenous leukemia.
Doses of Interferon Alfa-2b and Cytarabine and Compliance with the Protocol
One patient in the interferon–cytarabine group and twopatients in the interferon group were not treated with interferon.During the first 12 months of the study, the mean daily doseof interferon was 5.4 million units in the interferon–cytarabinegroup and 5.8 million units in the interferon group; the medianduration of treatment with interferon (as estimated by the Kaplan–Meiermethod) was 34 months in the interferon–cytarabine groupand 28 months in the interferon group. Among the 360 patientsassigned to receive interferon and cytarabine, 31 patients didnot receive cytarabine during the study period. During the first12 months, the median number of courses of cytarabine was 10(range, 1 to 12), and the mean daily dose of cytarabine administeredwas 30 mg. The median duration of treatment with cytarabinewas 14 months (range, 9 days to 52 months).
Among the 118 patients in the interferon group who crossed overto receive cytarabine, cytogenetic responses were recorded in18 (complete in 7 and partial in 11). According to the designof the study, allogeneic or autologous stem-cell transplantationwas performed in 105 patients with resistance to treatment:58 patients (22 in the interferon–cytarabine group and36 in the interferon group) received allogeneic marrow, and47 patients (24 in the interferon–cytarabine group and23 in the interferon group) received autologous stem cells.The two-year survival rate after allogeneic transplantationwas 56 percent in the interferon–cytarabine group and59 percent in the interferon group; after autologous transplantation,these rates were 61 percent and 68 percent, respectively. Themain causes of death were graft-versus-host disease after allogeneicbone marrow transplantation and blast crisis after autologousstem-cell transplantation (Table 3).
Toxicity and Side Effects
Major side effects led to the discontinuation of interferontreatment in 94 patients in the interferon–cytarabinegroup (Table 4). Cytarabine alone was assumed to have causedside effects in 85 patients, most commonly nausea, vomiting,diarrhea, and mucositis. The chief hematologic toxic effectof cytarabine was thrombocytopenia, but no life-threateningepisodes of bleeding were recorded. Skin rashes and irritationsat the sites of subcutaneous injections were attributed to cytarabine.In one patient hepatitis resolved after the discontinuationof cytarabine, although interferon treatment was continued.
Table 4. Major Side Effects That Led to the Discontinuation of Treatment, According to Treatment Assignment.
In the interferon group, adverse events prompted the discontinuationof interferon in 97 patients. The main side effects were myalgia,arthralgia, asthenia, weight loss, and headache. Moreover, severesymptoms of depression led to the discontinuation of interferonin patients in both groups. Among the 118 patients who crossedover to the combination treatment, 32 discontinued cytarabinebecause of side effects.
Discussion
In this sequential randomized trial, we found a survival benefitfor patients with chronic myelogenous leukemia in the chronicphase who were treated with interferon and cytarabine. Patientsgiven this combination also had higher rates of hematologicand cytogenetic responses than did patients who received onlyinterferon. Other investigators have also found that a majorcytogenetic response correlates with prolonged survival.5,6,7,21
The study design allowed patients in the interferon group tocross over to the interferon–cytarabine group if theydid not have complete hematologic responses by 6 months or majorcytogenetic responses by 12 months. Among the 118 patients whocrossed over to the combination treatment, 50 did so after 6to 12 months of treatment with interferon. Among these 50 patients,3 had partial cytogenetic responses and 1 had a complete response.Thus, the intention-to-treat comparison of the 6-month and 12-monthend points was not affected by the crossover. In addition, since31 patients in the interferon–cytarabine group did notactually receive cytarabine, the true benefit of cytarabinemay exceed that actually observed. Because of treatment failure,transplantation was performed during the first year in 7 patientsin the interferon–cytarabine group and 12 patients inthe interferon group; only 2 of these patients (both in theinterferon group) had major cytogenetic responses at one year.
We gave every study patient hydroxyurea beginning at the timeof diagnosis. The intent of this treatment was to lower theleukocyte count rapidly and reach hematologic remission quickly.Interferon alone requires a long period before its effects onthe blood count become apparent.
Differences among trials in the rates of cytogenetic responsemay be related to various factors, including the phase of thedisease, the patients' characteristics before treatment, thedose of interferon alfa, and the frequency of cytogenetic analysis.The Italian Cooperative Study Group reported an 8 percent rateof complete cytogenetic response and an 11 percent rate of partialresponse.5 They found that the time needed for the disease toprogress from the chronic phase to an accelerated or blasticphase was greater in the group treated with interferon thanin the group that received standard therapy.5 Other studieshave confirmed the survival benefit of interferon treatmenteven among patients with no cytogenetic response.6 However,Hehlmann et al., who found a 7 percent rate of complete cytogeneticresponse among patients treated with interferon alfa, did notobserve a significant survival advantage among patients whohad a cytogenetic response.22 Using a landmark approach anda time-dependent covariate model, Ozer et al. also failed tofind a correlation between cytogenetic responses and the durationof remission or survival.23 However, these discrepancies betweentrials have been explained.24
Because only a minority of patients treated with interferonhave a major cytogenetic response, additional strategies areneeded. In vitro studies suggested an additive effect of interferonand cytarabine.25 Patients in the advanced chronic phase ofchronic myelogenous leukemia who were treated with the combinationof interferon and cytarabine had a high incidence of hematologicremission and a trend toward a high rate of cytogenetic response,although the study was not randomized.26 This combination ofdrugs is currently under investigation in patients in the earlychronic phase of chronic myelogenous leukemia.27 In our study,a substantial number of patients discontinued the combined treatmentbecause of side effects, but the patients who were able to continuethe treatment had significantly better survival than those treatedwith interferon alone. Perhaps a new oral formulation of cytarabinewill have less toxicity than the form of the drug currentlyavailable.28
Supported by grants from the Programme Hospitalier de RechercheClinique, the Ligue Nationale contre le Cancer, the Associationpour la Recherche contre le Cancer, and Schering-Plough, France.
We are indebted to Nathalie Richetin and Chantal Delafond fortheir skillful assistance.
* Additional participating institutions, with their principalinvestigators, are listed in the Appendix.
Source Information
From Hôpital Jean Bernard, Poitiers (F.G., J.T.); Hôpital Saint-Louis, Paris (C.C.); Hôpital Edouard Herriot, Lyons (M.M.); Hôpital Brabois, Vandoeuvre-Les-Nancy (A.G.); Hôtel Dieu, Nantes (J.-L.H.); Hôpital de Hautepierre, Strasbourg (F.M.); Institut Paoli Calmette, Marseilles (R.B.); Hôpital Nord, Saint-Etienne (D.G.); Hôpital Saint-Antoine, Paris (N.C.); Hôpital Michalon, Grenoble (F.N.); and Hôpital Morvan, Brest (J.-F.A.) — all in France. Other authors were Maurice Navarro, M.D. (Hôpital Lapeyronie, Montpellier), Dominique Bordessoule, M.D. (Hôpital Dupuytren, Limoges), Patrick Morice, M.D. (Hôpital La Bauchée, Saint-Brieuc), Norbert Ifrah, M.D. (Hôpital Régional, Angers), Henri Rochant, M.D. (Hôpital Henri Mondor, Créteil), Jean-Pierre Vilque, M.D. (Hôpital Robert Debré, Reims), Martine Delain, M.D. (Hôpital Bretonneau, Tours), Francis Bauters, M.D. (Hôpital Claude Huriez, Lille), and Joëlle Guilhot, B.S. (Hôpital Jean Bernard, Poitiers).
Address reprint requests to Dr. Guilhot at the Department of Hematology and Medical Oncology, Hôpital Jean Bernard, 86021 Poitiers CEDEX, France.
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Appendix
The following additional centers and investigators in the FrenchChronic Myeloid Leukemia Study Group participated in the study:Amiens, Centre Hospitalier Régional Universitaire (CHRU)Hôpital Sud (B. Desablens); Amiens, Centre HospitalierUniversitaire (CHU) Nord (C. Traulle); Annecy, Centre Hospitalier(C. Martin); Avignon, Hôpital Henri Duffaut (G. Le Peu);Bayonne, Centre Hospitalier de la Côte Basque (F. Bauduer);Beauvais, Centre Hospitalier (J.L. Dutel); Bobigny, HôpitalAvicenne (P. Casassus); Bondy, Hôpital Jean Verdier (F.Lejeune); Bourg en Bresse, Centre Hospitalier Fleyriat (H. Orfeuvre);Châlon sur Saone, Centre Hospitalier (D. Baudet-Klepping);Chambéry, Centre Hospitalier (M. Blanc); Clamart, Hôpitald'Instruction des Armées de Percy (G. Nedellec); Clermont-Ferrand,Centre Jean Perrin (M. Legros); Clermont-Ferrand, HôpitalHôtel Dieu (F. Tavernier); Clichy, Hôpital Beaujon(J. Brière); Colmar, Centre Hospitalier Louis Pasteur(B. Audhuy, F. Kohser); Corbeil-Essonne, Centre Hospitalier(A. Devidas); Dunkerque, Centre Hospitalier (M. Wetterwald);La Roche sur Yon, Centre Hospitalier Départemental lesOudairies (H. Maisonneuve); Le Kremlin Bicêtre, Hôpitalde Bicêtre (G. Tertian); Le Mans, Centre Hospitalier (F.Duguay); Lyons, Hôpital Edouard Herriot (N. Philippe);Martigues, Centre Hospitalier (M. Nezri); Meaux, Centre Hospitalier(C. Allard and G. Netter-Pinon); Metz, Hôpital Notre Damedu Bon Secours (B. Christian); Metz, Hôpital Sainte Blandine(F. Rumilly); Montfermeil, Centre Hospitalier Intercommunal(M. Lenoble); Montpellier, Hôpital Lapeyronie (A.J. Ciurana);Mulhouse, Centre Hospitalier (J.C. Einsenmann); Nice, CentreAntoine Lacassagne (A. Thyss); Nice, Hôpital Cimiez (J.G.Fuzibet); Orléans, CHRU La Source (M. Schoenwald); Paris,Hôpital Bichat (M.J. Grange); Paris, Hôpital Cochin(F. Dreyfus); Paris, Hôpital La Pitié–Salpétrière(L. Sutton); Paris, Hôpital Lariboisière (J.M.Zini); Paris, Hôpital Necker (C. Belanger); Paris, HôpitalSaint-Louis (P. Brice, A. Devergie, H. Esperou-Bourdeau); PierreBénite, Centre Hospitalier Lyon Sud (B. Salles); Pontoise,Centre Hospitalier René Dubos (Y. Kerneis); Rennes, HôpitalSud (R. Leblay); Rouen, Centre Henri Becquerel (P. Piguet);Saint Etienne, Hôpital Nord (J. Jaubert); Saint-Cloud,Centre René Huguenin (F. Turpin and M. Janvier); Suresnes,Hôpital Foch (E. Baumelou); Troyes, Hôpital desHauts Clos (G. Dine); Valencienne, Centre Hospitalier (M. Simonand J.P. Pollet); Vannes, Hôpital Chubert (H. Jardel);Villejuif, Institut Gustave Roussy (E. Goldschmidt and M.P.Lemonnier).
The following members of the Groupe Français de CytogénétiqueHématologique performed the karyotyping: M.F. Bertheas,S. Briault, A. Brizard, C. Charrin, A. Dauvigon, P. Jonveaux,M. Lafage-Pochitaloff, J.L. Lai, J. Lespinasse, M. Lessard,M. Poissonnier, P. Talmant, F. Uettwiller, and J. van der Akker.
Castagnetti, F., Palandri, F., Amabile, M., Testoni, N., Luatti, S., Soverini, S., Iacobucci, I., Breccia, M., Rege Cambrin, G., Stagno, F., Specchia, G., Galieni, P., Iuliano, F., Pane, F., Saglio, G., Alimena, G., Martinelli, G., Baccarani, M., Rosti, G., for the GIMEMA CML Working Party,
(2009). Results of high-dose imatinib mesylate in intermediate Sokal risk chronic myeloid leukemia patients in early chronic phase: a phase 2 trial of the GIMEMA CML Working Party. Blood
113: 3428-3434
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Deenik, W., van der Holt, B., Verhoef, G. E. G., Smit, W. M., Kersten, M. J., Kluin-Nelemans, H. C., Verdonck, L. F., Ferrant, A., Schattenberg, A. V. M. B., Janssen, J. J. W. M., Sonneveld, P., van Marwijk Kooy, M., Wittebol, S., Willemze, R., Wijermans, P. W., Westveer, P. H. M., Beverloo, H. B., Valk, P., Lowenberg, B., Ossenkoppele, G. J., Cornelissen, J. J.
(2008). Dose-finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia. Blood
111: 2581-2588
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Kantarjian, H., Schiffer, C., Jones, D., Cortes, J.
(2008). Monitoring the response and course of chronic myeloid leukemia in the modern era of BCR-ABL tyrosine kinase inhibitors: practical advice on the use and interpretation of monitoring methods. Blood
111: 1774-1780
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Brave, M., Goodman, V., Kaminskas, E., Farrell, A., Timmer, W., Pope, S., Harapanhalli, R., Saber, H., Morse, D., Bullock, J., Men, A., Noory, C., Ramchandani, R., Kenna, L., Booth, B., Gobburu, J., Jiang, X., Sridhara, R., Justice, R., Pazdur, R.
(2008). Sprycel for Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Resistant to or Intolerant of Imatinib Mesylate. Clin. Cancer Res.
14: 352-359
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Schiffer, C. A.
(2007). BCR-ABL Tyrosine Kinase Inhibitors for Chronic Myelogenous Leukemia. NEJM
357: 258-265
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Guilhot, F.
(2007). No more transplantation in CML?. Blood
109: 4592-4592
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Hochhaus, A., Kantarjian, H. M., Baccarani, M., Lipton, J. H., Apperley, J. F., Druker, B. J., Facon, T., Goldberg, S. L., Cervantes, F., Niederwieser, D., Silver, R. T., Stone, R. M., Hughes, T. P., Muller, M. C., Ezzeddine, R., Countouriotis, A. M., Shah, N. P.
(2007). Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood
109: 2303-2309
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Steensma, D. P., Richard, R. E.
(2007). Myeloproliferative disorders. ASH-SAP
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Kantarjian, H. M., Talpaz, M., Giles, F., O'Brien, S., Cortes, J.
(2006). New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance. ANN INTERN MED
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Druker, B. J., Guilhot, F., O'Brien, S. G., Gathmann, I., Kantarjian, H., Gattermann, N., Deininger, M. W.N., Silver, R. T., Goldman, J. M., Stone, R. M., Cervantes, F., Hochhaus, A., Powell, B. L., Gabrilove, J. L., Rousselot, P., Reiffers, J., Cornelissen, J. J., Hughes, T., Agis, H., Fischer, T., Verhoef, G., Shepherd, J., Saglio, G., Gratwohl, A., Nielsen, J. L., Radich, J. P., Simonsson, B., Taylor, K., Baccarani, M., So, C., Letvak, L., Larson, R. A., the IRIS Investigators,
(2006). Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia. NEJM
355: 2408-2417
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Frame, D.
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Baccarani, M., Saglio, G., Goldman, J., Hochhaus, A., Simonsson, B., Appelbaum, F., Apperley, J., Cervantes, F., Cortes, J., Deininger, M., Gratwohl, A., Guilhot, F., Horowitz, M., Hughes, T., Kantarjian, H., Larson, R., Niederwieser, D., Silver, R., Hehlmann, R.
(2006). Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood
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Roy, L., Guilhot, J., Krahnke, T., Guerci-Bresler, A., Druker, B. J., Larson, R. A., O'Brien, S., So, C., Massimini, G., Guilhot, F.
(2006). Survival advantage from imatinib compared with the combination interferon-{alpha} plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials. Blood
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Quintas-Cardama, A., Cortes, J. E.
(2006). Chronic Myeloid Leukemia: Diagnosis and Treatment. Mayo Clin Proc.
81: 973-988
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Mistler, L. A., Brunette, M. F., Marsh, B. J., Vidaver, R. M., Luckoor, R., Rosenberg, S. D.
(2006). Hepatitis C treatment for people with severe mental illness.. Psychosomatics
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Guilhot, F., Roy, L., Guilhot, J., Krahnke, T., Guerci, A., Druker, B., Larson, R., O'Brien, S., So, C., Massimini, G.
(2005). Retrospective Comparison of Imatinib Versus Interferon Plus Cytarabine (IFN/Ara-c) for Chronic Myelogenous Leukemia (CML) Patients in Chronic Phase (CP).. ASH ANNUAL MEETING ABSTRACTS
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Talpaz, M., Rakhit, A., Rittweger, K., O'Brien, S., Cortes, J., Fettner, S., Hooftman, L., Kantarjian, H.
(2005). Phase I Evaluation of a 40-kDa Branched-Chain Long-Acting Pegylated IFN-{alpha}-2a With and Without Cytarabine in Patients with Chronic Myelogenous Leukemia. Clin. Cancer Res.
11: 6247-6255
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Millot, F., Traore, P., Guilhot, J., Nelken, B., Leblanc, T., Leverger, G., Plantaz, D., Bertrand, Y., Bordigoni, P., Guilhot, F.
(2005). Clinical and Biological Features at Diagnosis in 40 Children With Chronic Myeloid Leukemia. Pediatrics
116: 140-143
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Tefferi, A., Dewald, G. W., Litzow, M. L., Cortes, J., Mauro, M. J., Talpaz, M., Kantarjian, H. M.
(2005). Chronic Myeloid Leukemia: Current Application of Cytogenetics and Molecular Testing for Diagnosis and Treatment. Mayo Clin Proc.
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Baccarani, M., Martinelli, G., Rosti, G., Trabacchi, E., Testoni, N., Bassi, S., Amabile, M., Soverini, S., Castagnetti, F., Cilloni, D., Izzo, B., de Vivo, A., Messa, E., Bonifazi, F., Poerio, A., Luatti, S., Giugliano, E., Alberti, D., Fincato, G., Russo, D., Pane, F., Saglio, G., for the GIMEMA Working Party on Chronic Myeloid Le,
(2004). Imatinib and pegylated human recombinant interferon-{alpha}2b in early chronic-phase chronic myeloid leukemia. Blood
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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.
(2004). Interferon-{alpha}-2b and oral cytarabine ocfosfate for newly diagnosed chronic myeloid leukaemia. Ann Oncol
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Kantarjian, H. M., Cortes, J. E., O'Brien, S., Luthra, R., Giles, F., Verstovsek, S., Faderl, S., Thomas, D., Garcia-Manero, G., Rios, M. B., Shan, J., Jones, D., Talpaz, M.
(2004). Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-{alpha}. Blood
104: 1979-1988
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Kluin-Nelemans, H. C., Buck, G., le Cessie, S., Richards, S., Beverloo, H. B., Falkenburg, J. H. F., Littlewood, T., Muus, P., Bareford, D., van der Lelie, H., Green, A. R., Roozendaal, K. J., Milne, A. E., Chapman, C. S., Shepherd, P.
(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
103: 4408-4415
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Stone, R. M.
(2004). Optimizing Treatment of Chronic Myeloid Leukemia: A Rational Approach. The Oncologist
9: 259-270
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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
103: 2873-2878
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Gardembas, M., Rousselot, P., Tulliez, M., Vigier, M., Buzyn, A., Rigal-Huguet, F., Legros, L., Michallet, M., Berthou, C., Cheron, N., Maloisel, F., Mahon, F.-X., Facon, T., Berthaud, P., Guilhot, J., Guilhot, F.
(2003). Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase. Blood
102: 4298-4305
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Hughes, T. P., Kaeda, J., Branford, S., Rudzki, Z., Hochhaus, A., Hensley, M. L., Gathmann, I., Bolton, A. E., van Hoomissen, I. C., Goldman, J. M., Radich, J. P., the International Randomised Study of Interferon v,
(2003). Frequency of Major Molecular Responses to Imatinib or Interferon Alfa plus Cytarabine in Newly Diagnosed Chronic Myeloid Leukemia. NEJM
349: 1423-1432
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Goldman, J. M., Melo, J. V.
(2003). Chronic Myeloid Leukemia -- Advances in Biology and New Approaches to Treatment. NEJM
349: 1451-1464
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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.
(2003). Imatinib improves but may not fully reverse the poor prognosis of patients with CML with derivative chromosome 9 deletions. Blood
102: 2205-2212
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Deininger, M. W. N., Druker, B. J.
(2003). Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib. Pharmacol. Rev.
55: 401-423
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Antin, J. H.
(2003). A 41-Year-Old Woman With Chronic Myelogenous Leukemia. JAMA
290: 1083-1090
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Huntly, B. J. P., Bench, A., Green, A. R.
(2003). Double jeopardy from a single translocation: deletions of the derivative chromosome 9 in chronic myeloid leukemia. Blood
102: 1160-1168
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Radich, J. P., Gooley, T., Bensinger, W., Chauncey, T., Clift, R., Flowers, M., Martin, P., Slattery, J., Sultan, D., Appelbaum, F. R.
(2003). HLA-matched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen. Blood
102: 31-35
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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.
(2003). Result of high-dose imatinib mesylate in patients with Philadelphia chromosome--positive chronic myeloid leukemia after failure of interferon-{alpha}. Blood
102: 83-86
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Johnson, J. R., Bross, P., Cohen, M., Rothmann, M., Chen, G., Zajicek, A., Gobburu, J., Rahman, A., Staten, A., Pazdur, R.
(2003). Approval Summary: Imatinib Mesylate Capsules for Treatment of Adult Patients with Newly Diagnosed Philadelphia Chromosome-positive Chronic Myelogenous Leukemia in Chronic Phase. Clin. Cancer Res.
9: 1972-1979
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Cortes, J. E., Talpaz, M., Giles, F., O'Brien, S., Rios, M. B., Shan, J., Garcia-Manero, G., Faderl, S., Thomas, D. A., Wierda, W., Ferrajoli, A., Jeha, S., Kantarjian, H. M.
(2003). Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy. Blood
101: 3794-3800
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Uno, K., Inukai, T., Kayagaki, N., Goi, K., Sato, H., Nemoto, A., Takahashi, K., Kagami, K., Yamaguchi, N., Yagita, H., Okumura, K., Koyama-Okazaki, T., Suzuki, T., Sugita, K., Nakazawa, S.
(2003). TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome-positive leukemia cells. Blood
101: 3658-3667
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O'Brien, S. G., Guilhot, F., Larson, R. A., Gathmann, I., Baccarani, M., Cervantes, F., Cornelissen, J. J., Fischer, T., Hochhaus, A., Hughes, T., Lechner, K., Nielsen, J. L., Rousselot, P., Reiffers, J., Saglio, G., Shepherd, J., Simonsson, B., Gratwohl, A., Goldman, J. M., Kantarjian, H., Taylor, K., Verhoef, G., Bolton, A. E., Capdeville, R., Druker, B. J., the IRIS Investigators,
(2003). Imatinib Compared with Interferon and Low-Dose Cytarabine for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia. NEJM
348: 994-1004
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Hole, A., Blake, D.
(2003). A review of imatinib mesilate in the treatment of patients with gastrointestinal stromal tumours and chronic myeloid leukaemia. J Oncol Pharm Pract
9: 1-14
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Tanvetyanon, T., Stadtmauer, E. A, Kerson, L. A
(2003). Concurrent Administration of Interferon Alfa-2b and Beta-1a. The Annals of Pharmacotherapy
37: 77-79
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Kantarjian, H. M., Talpaz, M., Cortes, J., O'Brien, S., Faderl, S., Thomas, D., Giles, F., Rios, M. B., Shan, J., Arlinghaus, R.
(2003). Quantitative Polymerase Chain Reaction Monitoring of BCR-ABL during Therapy with Imatinib Mesylate (STI571; Gleevec) in Chronic-Phase Chronic Myelogenous Leukemia. Clin. Cancer Res.
9: 160-166
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Kusy, S., Cividin, M., Sorel, N., Brizard, F., Guilhot, F., Brizard, A., Larsen, C., Roche, J.
(2003). p14ARF, p15INK4b, and p16INK4a methylation status in chronic myelogenous leukemia. Blood
101: 374-374
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Kantarjian, H. M., Cortes, J. E., O'Brien, S., Giles, F., Garcia-Manero, G., Faderl, S., Thomas, D., Jeha, S., Rios, M. B., Letvak, L., Bochinski, K., Arlinghaus, R., Talpaz, M.
(2003). Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses. Blood
101: 97-100
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Kantarjian, H. M., Talpaz, M., O'Brien, S., Smith, T. L., Giles, F. J., Faderl, S., Thomas, D. A., Garcia-Manero, G., Issa, J.-P. J., Andreeff, M., Kornblau, S. M., Koller, C., Beran, M., Keating, M., Rios, M. B., Shan, J., Resta, D., Capdeville, R., Hayes, K., Albitar, M., Freireich, E. J., Cortes, J. E.
(2002). Imatinib Mesylate for Philadelphia Chromosome-positive, Chronic-Phase Myeloid Leukemia after Failure of Interferon-{alpha}: Follow-Up Results. Clin. Cancer Res.
8: 2177-2187
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Cohen, M. H., Williams, G., Johnson, J. R., Duan, J., Gobburu, J., Rahman, A., Benson, K., Leighton, J., Kim, S. K., Wood, R., Rothmann, M., Chen, G., U, K. M., Staten, A. M., Pazdur, R.
(2002). Approval Summary for Imatinib Mesylate Capsules in the Treatment of Chronic Myelogenous Leukemia. Clin. Cancer Res.
8: 935-942
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O'Dwyer, M.
(2002). Multifaceted Approach to the Treatment of Bcr-Abl-Positive Leukemias. The Oncologist
7: 30-38
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Weisdorf, D. J., Anasetti, C., Antin, J. H., Kernan, N. A., Kollman, C., Snyder, D., Petersdorf, E., Nelson, G., McGlave, P.
(2002). Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation. Blood
99: 1971-1977
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Baccarani, M., Rosti, G., de Vivo, A., Bonifazi, F., Russo, D., Martinelli, G., Testoni, N., Amabile, M., Fiacchini, M., Montefusco, E., Saglio, G., Tura, S.
(2002). A randomized study of interferon-alpha versus interferon-alpha and low-dose arabinosyl cytosine in chronic myeloid leukemia. Blood
99: 1527-1535
[Abstract][Full Text]
Kantarjian, H., Sawyers, C., Hochhaus, A., Guilhot, F., Schiffer, C., Gambacorti-Passerini, C., Niederwieser, D., Resta, D., Capdeville, R., Zoellner, U., Talpaz, M., Druker, B., the International STI571 CML Study Group,
(2002). Hematologic and Cytogenetic Responses to Imatinib Mesylate in Chronic Myelogenous Leukemia. NEJM
346: 645-652
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Savage, D. G., Antman, K. H.
(2002). Imatinib Mesylate -- A New Oral Targeted Therapy. NEJM
346: 683-693
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Stull, D. M.
(2002). Current Trends in the Treatment of Acute and Chronic Myelogenous Leukemia. Journal of Pharmacy Practice
15: 62-74
[Abstract]
Moulignier, A., Allo, S., Zittoun, R., Gout, O.
(2002). Recombinant interferon-{alpha}-induced chorea and frontal subcortical dementia. Neurology
58: 328-329
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Lee, S. J., Klein, J. P., Anasetti, C., Antin, J. H., Loberiza, F. R., Bolwell, B. J., LeMaistre, C. F., Litzow, M. R., Marks, D., Waller, E. K., Matlack, M., Giralt, S., Horowitz, M. M.
(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
98: 3205-3211
[Abstract][Full Text]
Bonifazi, F., de Vivo, A., Rosti, G., Guilhot, F., Guilhot, J., Trabacchi, E., Hehlmann, R., Hochhaus, A., Shepherd, P. C. A., Steegmann, J. L., Kluin-Nelemans, H. C., Thaler, J., Simonsson, B., Louwagie, A., Reiffers, J., Mahon, F. X., Montefusco, E., Alimena, G., Hasford, J., Richards, S., Saglio, G., Testoni, N., Martinelli, G., Tura, S., Baccarani, M.
(2001). Chronic myeloid leukemia and interferon-alpha : a study of complete cytogenetic responders. Blood
98: 3074-3081
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Talpaz, M., O'Brien, S., Rose, E., Gupta, S., Shan, J., Cortes, J., Giles, F. J., Faderl, S., Kantarjian, H. M.
(2001). Phase 1 study of polyethylene glycol formulation of interferon {alpha}-2B (Schering 54031) in Philadelphia chromosome-positive chronic myelogenous leukemia. Blood
98: 1708-1713
[Abstract][Full Text]
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
98: 1732-1738
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Kalidas, M., Kantarjian, H., Talpaz, M.
(2001). Chronic Myelogenous Leukemia. JAMA
286: 895-898
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Schmidt, M., Hochhaus, A., Nitsche, A., Hehlmann, R., Neubauer, A.
(2001). Expression of nuclear transcription factor interferon consensus sequence binding protein in chronic myeloid leukemia correlates with pretreatment risk features and cytogenetic response to interferon-{alpha}. Blood
97: 3648-3650
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Jonasch, E., Haluska, F. G.
(2001). Interferon in Oncological Practice: Review of Interferon Biology, Clinical Applications, and Toxicities. The Oncologist
6: 34-55
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Druker, B. J., Sawyers, C. L., Capdeville, R., Ford, J. M., Baccarani, M., Goldman, J. M.
(2001). Chronic Myelogenous Leukemia. ASH Education Book
2001: 87-112
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Thiesing, J. T., Ohno-Jones, S., Kolibaba, K. S., Druker, B. J.
(2000). Efficacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl-positive cells. Blood
96: 3195-3199
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Kantarjian, H. M., Talpaz, M., Smith, T. L., Cortes, J., Giles, F. J., Rios, M. B., Mallard, S., Gajewski, J., Murgo, A., Cheson, B., O'Brien, S.
(2000). Homoharringtonine and Low-Dose Cytarabine in the Management of Late Chronic-Phase Chronic Myelogenous Leukemia. JCO
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Le Gouill, S., Talmant, P., Milpied, N., Daviet, A., Ancelot, M., Moreau, P., Harousseau, J.-L., Bataille, R., Avet-Loiseau, H.
(2000). Fluorescence In Situ Hybridization on Peripheral-Blood Specimens Is a Reliable Method to Evaluate Cytogenetic Response in Chronic Myeloid Leukemia. JCO
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