Journal of Clinical Oncology, Vol 17, Issue 1
(January), 1999: 284
© 1999 American Society for Clinical Oncology
Treatment of Philadelphia Chromosome-Positive Early Chronic Phase Chronic Myelogenous Leukemia With Daily Doses of Interferon Alpha and Low-Dose Cytarabine
Hagop M. Kantarjian,
Susan O'Brien,
Terry L. Smith,
Mary Beth Rios,
Jorge Cortes,
Miloslav Beran,
Charles Koller,
Francis J. Giles,
Michael Andreeff,
Steven Kornblau,
Sergio Giralt,
Michael J. Keating,
Moshe Talpaz
From the Departments of Leukemia, Biostatistics, Bone Marrow Transplantation, and Bioimmunotherapy, M.D. Anderson Cancer Center, Houston, TX.
Address reprint requests to Hagop M. Kantarjian, M.D. Anderson Cancer Center, Department of Hematology, Box 61, 1515 Holcombe Blvd, Houston, TX 77030.
 |
ABSTRACT
|
|---|
PURPOSE: To evaluate the efficacy of the combination of interferon alpha (IFN- ) and daily low-dose cytarabine (ara-C) in the treatment of patients with early chronic-phase chronic myelogenous leukemia (CML) (within 1 year of diagnosis). Improving the degree of hematologic and cytogenetic response in patients with Philadelphia chromosome (Ph)-positive CML may improve prognosis. Both IFN- and ara-C induce cytogenetic responses as single-agent therapy in CML.
PATIENTS AND METHODS: One hundred forty patients with Ph-positive early chronic-phase CML received subcutaneous injections of IFN- 5 megaunits/m2 daily and ara-C 10 mg daily. Their median age was 46 years; 53% had good-risk disease, 33% had intermediate-risk disease, and 14% had poor-risk disease. Their results were compared with those of patients receiving IFN- with or without intermittent ara-C (7 days/mo).
RESULTS: A complete hematologic response (CHR) was achieved in 92% of patients. A cytogenetic response was seen in 74%: it was major in 50% (Ph-positive < 35%) and complete in 31% (Ph-positive 0%). With a median follow-up of 42 months, the 4-year estimated survival rate was 70% (95% confidence interval, 61% to 79%). Significant side effects included fatigue (43%; grade 3/4, 11%), weight loss (19%; grade 3/4, 11%), muscle and bone aches (20%; grade 3/4, 7%), oral ulcers (4%), diarrhea (6%), and neurologic changes (27%, grade 3/4, 6%). The median dose of IFN- was 3.7 megaunits/m2 daily, mainly because of reductions for myelosuppression (70% of cases); the median ara-C dose was 7.5 mg daily. Prognostic risk groups were predictive for response to the IFN- plus ara-C combination. The incidence of CHR was higher with IFN- plus daily ara-C compared with IFN- plus intermittent ara-C and IFN- alone (no ara-C) (92% v 84% v 80%, P = .01), as were the incidences of cytogenetic response (74% v 73% v 58%; P = .003) and major cytogenetic response (50% v 38% v 38%; P = .06). The median time to achievement of major cytogenetic response was significantly shorter than that for previous IFN- regimens (7 v 10 v 12 months; P < .01). However, with the present follow-up, the survival and time to blastic transformation were similar.
CONCLUSION: The combination of IFN- plus daily low-dose ara-C seems to be promising for the treatment of CML. High rates of CHR and cytogenetic response were observed with acceptable toxicity and a lower daily dose of IFN- compared with our previous studies.
|
INTRODUCTION
|
|---|
PROGNOSIS IN Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) has improved.1 The median survival time has increased from 3 years to 7 years. This increase has been attributed to earlier diagnosis and to improved therapy with modalities such as allogeneic stem-cell transplantation (SCT) and interferon alpha (IFN-).2-9
The positive results with investigations aimed at suppressing the Ph-positive clones have been further supported by animal models demonstrating the causal association between the Ph-related molecular abnormalities and the development of CML.10-13 Interferon alpha, outside the setting of allogeneic SCT, is the first modality to provide significant durable suppression of Ph-positive clones. In our studies, IFN- therapy induced complete hematologic remissions (CHRs) in 70% to 80% of patients and Ph-positive clonal suppression (cytogenetic response) in more than 50%; the clonal suppression was major (Ph-positive lowest value < 35%) in 38%, and durable in 25%.5 Responses in most6-9 but not all studies14 were lower, perhaps because of different population characteristics, risk group distributions, study designs, dose schedules of IFN- delivered, patient-physician enthusiasm, and tolerance of side effects.15-17 In most studies, there was an association between achievement of cytogenetic response and survival improvement, which was confirmed by landmark and multivariate analysis techniques.5,6,8,14
Improving the degree of cytogenetic response and reducing treatment side effects may further improve prognosis in CML. Cytarabine (ara-C) suppressed CML clones selectively in vitro18 and induced cytogenetic responses in seven of nine patients with CML treated with low-dose ara-C.19,20 Studies of IFN- plus low-dose ara-C in late chronic-phase CML21 and in earlier phases were encouraging.22,23 Most studies have used intermittent low-dose ara-C schedules (eg, ara-C 10 to 20 mg/m2 daily for 7 to 14 days every month).21-25 Unlike intensive chemotherapy,26-28 low-dose ara-C is safer and can be continued for longer periods of time.
Our first study of late and early chronic-phase CML used intermittent ara-C schedules of 15 mg/m2 daily for 7 days every month. In 1993, we modified the ara-C schedule to a daily dose of 10 mg with IFN- to expose CML cells to the effect of ara-C 100% of the time rather than 25% of the time. In this article, we summarize our experience with the daily schedule of IFN- and low-dose ara-C in early chronic-phase CML.
|
PATIENTS AND METHODS
|
|---|
Study Group
Adults with a diagnosis of Ph-positive early chronic-phase CML who were referred to our institution from 1993 until January 1996 were entered onto our study. Participants were consecutive patients who were eligible for the study and who agreed to undergo the investigational treatment. Informed consent was obtained according to institutional guidelines. Entry criteria were (1) confirmation of Ph-positive disease by cytogenetic analysis in early chronic phase (diagnosis to start of therapy,  12 months)1; (2) age 15 years or older; (3) performance score of 0 to 3 (Zubrod scale); (4) adequate cardiac, hepatic (bilirubin 3 mg/100 mL), and renal functions (creatinine 2 mg/100 mL); and (5) no prior neuropsychiatric disorders. Patients in the late chronic phase, accelerated phase (except for cytogenetic clonal evolution),29,30 and blastic phase who were treated in this study will be reported separately.
Patients underwent a pretreatment work-up that included the following: history and physical examination; complete blood, platelet, and differential counts; serum chemistry analyses (SMA 12), including liver and renal function studies; and bone marrow aspiration, biopsy, and chromosomal studies on at least 20 metaphases when possible.31 Other studies were conducted as indicated by the clinical condition.
Follow-up studies included the following: complete blood, platelet, and differential counts one to two times a week until remission, then every 2 to 4 weeks; SMA 12 weekly until remission, then every 2 to 4 weeks; and bone marrow aspiration and chromosomal studies every 3 months in the first year, then every 3 to 6 months thereafter.
Comparative Groups
Patients were compared with two previous cohorts of patients: (1) patients treated with IFN- alone or IFN- in combination with gamma interferon or hydroxyurea between 1982 and 1989,5 and (2) patients treated between 1989 and 1991 with IFN- plus intermittent low-dose ara-C 15 mg/m2 daily for 7 days every month.
Therapy
From 1993 until the present, patients have been treated with IFN- 5 megaunits/m2 subcutaneously (SC) daily and ara-C 10 mg SC daily (DM93–50). To allow sufficient follow-up, this analysis includes only patients entered onto the study through January 1996. Hydroxyurea 1 to 5 g orally daily was allowed initially to reduce the WBC counts below 30 x 109/L. Interferon alpha was started at 3 megaunits daily for 3 to 7 days and then increased to 5 megaunits/m2 daily according to tolerance in the first 2 weeks. Hydroxyurea could be used in the first 2 months of therapy to keep the WBC count below 20 x 109/L.
The treatment schedules of patients treated with IFN- before 1989 have previously been described.5 Between 1989 and 1991, patients were treated with IFN- 5 megaunits/m2 SC daily and ara-C 15 mg/m2 daily for 7 days every month, given in two equal subcutaneous doses (DM87–54). Between 1991 and 1993, patients were treated on a separate program of homoharringtonine and IFN-; these results are reported separately.32
Dose Adjustments
For IFN-–associated side effects (fatigue, depression, neurotoxicity, insomnia, etc.), the IFN- dose was reduced by 25% for grade 2 chronic side effects. For grade 3/4 side effects, IFN- was interrupted and resumed at 50% of the previous dose after resolution of side effects.
For ara-C–associated side effects (diarrhea and mucositis), the ara-C dose was reduced by 2 days on the intermittent ara-C schedule and by 25% for grade 2 or 50% for grade 3/4 side effects on the daily ara-C schedule.
The intermittent ara-C schedule was adjusted by ± 2 days to achieve a lowest granulocyte count of about 109/L, with platelets remaining above 40 x 109/L with each monthly cycle. On the daily IFN- and ara-C schedule, both IFN- and ara-C were reduced by 25% if the granulocyte count fell below 109/L or the platelet count fell below 50 x 109/L. Once the dose of IFN- was at 2.5 megaunits/m2 daily (level 2), the ara-C dose was reduced (to 5 mg every other day) without reducing the IFN- dose.
Toxicity criteria were in accordance with guidelines of the National Cancer Institute.33
Response
Response criteria were as previously described.5 A CHR required the disappearance of all signs and symptoms of disease, including palpable splenomegaly and normalization of peripheral counts (WBC count < 10 x 109/L), normal differential counts (absence of blasts, promyelocytes, myelocytes, and metamyelocytes), and normal platelet counts (< 450 x 109/L). Patients who achieved CHR were categorized by the degree of cytogenetic response (complete [Ph 0%], partial [Ph 1% to 34%], or minor [Ph 35% to 90%]), according to the lowest percentage of Ph-positive cells. Complete and partial cytogenetic responses are referred to as major cytogenetic responses (Ph < 35%).
Statistical Analyses
Survival curves were estimated by the method of Kaplan and Meier, with survival measured from the date treatment started until death from any cause.34 Response rates were compared using the  2 and Wilcoxon tests, and differences were analyzed in all three subgroups and among survival curves with the log-rank test.35 Patient risk groups were defined as previously described,5,36 using the "overall" model, which was developed at our institution and based on analysis of our referral population.36 The validity of the overall model was confirmed in a subsequent study group.5 An event chart was used to display the sequence of timed events for the subset of patients who experienced events (Lee JJ, Hess KR, Dubin JA: Extensions and applications of event charts, submitted for publication).
|
RESULTS
|
|---|
Study Group
One hundred forty patients were entered onto the study. Pretreatment patient characteristics are listed in Table 1. Fifty-three percent of patients had good-risk disease, 33% had intermediate-risk disease, and 14% had poor-risk disease. Cytogenetic clonal evolution was present at diagnosis in 13 patients (9%).
Response
One hundred thirty-four of the 140 patients treated with IFN-A and daily ara-C were assessable for response. Six could not be unassessed: four never started on therapy, and two stopped after 2 and 6 weeks without available response data. Overall, 92% of patients achieved CHR. A cytogenetic response was observed in 74% of patients and was major in 50% and complete in 31%.
Table 2 compares the response data for the IFN- and intermittent ara-C regimen and the IFN- without ara-C regimen. Despite the shorter median follow-up on the IFN- plus daily ara-C study, the rates of CHR, cytogenetic response, and major cytogenetic response were higher with IFN- plus daily ara-C. Additional major and complete cytogenetic responses may be noted with further follow-up. Among the 67 patients who have responded so far, the median time to major cytogenetic response was 12 months with IFN- alone (n = 104) and 10 months with IFN- and intermittent ara-C (n = 18) but only 7 months with IFN- and daily ara-C (P = .0003).
Survival
The overall estimated survival rate at 4 years was 70% (95% confidence interval, 61% to 79%; Fig 1). When data were censored at the time of transplantation for the 18 patients who underwent allogeneic SCT in chronic phase, the curve was better (estimated 4-year survival rate, 76%) because of early transplant mortality.
View larger version (15K):
[in this window]
[in a new window]
|
Fig 1. Survival probability with IFN- plus daily low-dose ara-C without censoring (solid line) and with censoring (dotted line) for the 18 patients who underwent bone marrow transplantation (BMT) while in chronic-phase CML.
|
|
Side Effects
The most significant side effects included fatigue and neurotoxicity (Table 3). Although it is sometimes difficult to distinguish between side effects related to either IFN- or ara-C, side effects such as diarrhea and mucositis were attributable to ara-C and neurotoxicity was attributable to IFN-; fatigue was probably attributable to both but was more likely caused by IFN-.
The median dose of IFN- was 3.7 megaunits/m2 daily. The IFN- dose schedule reductions (70% of reduction) were often caused by significant regimen-related myelosuppression (granulocytes < 109/L, platelets < 50 x 109/L) and, less commonly, IFN-–associated side effects. The median dose of ara-C was 7.5 mg daily.
Outcome of Patients With Initial Clonal Evolution
Among 13 patients with pretreatment cytogenetic clonal evolution, 12 (92%) achieved CHR, and 11 (85%) had a cytogenetic response (complete, n = 3; partial, n = 4; minor, n = 4). Disappearance of clonal evolution was observed in six patients (two of five patients with double Ph and four of eight patients with other abnormalities). At the time of last follow-up, nine patients were in chronic phase; four were on therapy, and five were on other therapies (three were taken off IFN- plus ara-C because of resistance and two because of toxicity). So far, one patient developed blastic transformation and died from its complications after matched unrelated donor (MUD) transplantation; three patients died of other causes (two after SCT and one with an aortic aneurysm).
Patients' Status
The event chart in Fig 2 shows patients' status. Twenty-nine patients developed accelerated phase CML (18 with clonal evolution only and 11 with other features). Seven patients evolved into the blastic phase, with two patients surviving allogeneic SCT (one related transplantation and one MUD transplantation): Of the 22 remaining patients, 14 are alive (11 with clonal evolution, three after allogeneic SCT [1 related, 2 MUD]). Eight patients died (three patients died after allogeneic SCT, three after MUD transplantation, and two of other causes).
View larger version (37K):
[in this window]
[in a new window]
|
Fig 2. Patient course and status of 59 patients who experienced events (death, transformation) or underwent allogeneic stem-cell transplantation (ACC, accelerated; BC, blastic phase).
|
|
Thirteen patients have developed blastic phase CML, seven after an accelerated phase. The morphology of the blastic phase was lymphoid in two patients (15%). Of the 13 patients, ten are dead, five died after allogeneic (four patients) or MUD transplantation (one patient) and five died as a result of blastic-phase complications.
Overall, 36 patients have died, including the 18 patients described above (eight deaths in the accelerated phase, 10 deaths in the blastic phase) and 18 patients who died in the chronic phase. Death in the chronic phase was caused by post-allogeneic SCT complications (five patients), post-MUD complications (seven patients), and other causes (six patients: one mesothelioma, one infection, two others, two unknown).
Eighteen patients underwent allogeneic (n = 10) or MUD transplantation (n = 8) in the chronic phase: six (33%) are alive (five [50%] of 10 related and one [12%] of eight MUD, with no evidence of disease) and 12 have died (five related, seven MUD). As detailed above, three (21%) of 14 patients who received allogeneic SCT (eight patients) or MUD transplantation (six patients) for the accelerated (n = 11) or blastic phase (n = 3) are alive.
At a median follow-up of 42 months, 104 (74%) of the 140 patients were alive. Eighty-seven remained in the chronic phase (57 on therapy [including nine of the original 13 who started with clonal evolution] and 30 off therapy [six after allogeneic bone marrow transplantation, 24 on other treatments]). Fourteen were in the accelerated phase (clonal evolution only, n = 11; after bone marrow transplantation, n = 3) and three were in the blastic phase.
Of the 57 patients in the chronic phase who were receiving therapy, 36 achieved a complete cytogenetic response as their best response, eight had a partial cytogenetic response, eight had a minor cytogenetic response, four had a CHR, and one a partial hematologic response (Table 4).
Association of Cytogenetic Response With Survival
To assess the association between degree of cytogenetic response and survival outcomes, a landmark analysis of 12-month response status versus subsequent survival was performed. This method reduces the impact of the delay time for observing cyto- genetic response. Only patients alive at 12 months were evaluated. Figure 3 depicts the association between response status at 12 months and survival. The estimated 4-year survival rate was 90% for major cytogenetic response, 73% for minor cytogenetic response and CHR, and 55% for other responses (P < .01).
View larger version (17K):
[in this window]
[in a new window]
|
Fig 3. Landmark analysis of 12-month response versus subsequent survival (CR, complete response; PR, partial response).
|
|
Comparison of IFN- Plus Daily Low-Dose Ara-C With IFN- Plus Intermittent Ara-C or IFN-A Without Ara-C
The incidences of CHR, cytogenetic response, and major cytogenetic response were significantly higher with IFN- plus daily ara-C (Table 2). The incidence of CHR was 92% with daily ara-C, 84% with intermittent ara-C, and 80% without ara-C (P = .01). The incidences of cytogenetic responses were 74% with daily ara-C, 73% with intermittent ara-C, and 58% without ara-C (P = .003). The incidences of major cytogenetic responses were 50% with daily ara-C, 38% with intermittent ara-C, and 38% without ara-C (P = .06). There was no apparent survival advantage at the time of analysis (Fig 4). In fact, the two most recent studies of IFN- and ara-C have a slightly worse survival in the early follow-up after 1 year because of the application of allogeneic SCT and MUD transplantation in patients who did not achieve a cytogenetic response after 12 months. This strategy had not been applied as often and as early in the IFN-–alone studies. When censoring for SCT in chronic phase, the survival curves were better with IFN- and ara-C (Fig 1), similar with IFN- alone, and similar with IFN- plus ara-C compared with IFN- with no ara-C (Figs 1 and 4).
The median daily dose of IFN- with daily-dose ara-C was lower (IFN- 3.7 megaunits/m2 daily plus ara-C 7.5 mg daily = 225 mg/mo) compared with the IFN- plus intermittent ara-C schedule (IFN- 5 megaunits/m2 daily plus ara-C 15 mg/m2 daily for 7 days = 105 mg/m2 [180 mg/mo]). The side effects of the two regimens were not different (data not shown), except that the incidences of anemia, thrombocytopenia, mucositis, and diarrhea were higher with the IFN- plus ara-C schedules.
Prognostic Risk Group, Response, and Survival With Therapy
Prognostic risk groups have previously been shown to predict for response and survival in IFN- therapy in large study groups with long-term follow-up.5 The outcomes of all patients, by risk groups in relation to response to therapy, are listed in Table 5. Although patients classified as being at higher risk were significantly less likely to achieve a cytogenetic response (P = .045 to .06), the current follow-up did not show major differences in survival (data not shown), although this may become apparent with longer follow-up.
|
DISCUSSION
|
|---|
Results obtained using this regimen of daily doses of both IFN- and low-dose ara-C were better than those achieved with IFN- without ara-C or IFN- with intermittent ara-C (7 days every month). Results were obtained significantly faster and with a lower dose schedule of IFN- (median 3.7 megaunits/m2 daily) without significant increased toxicity. Our results were similar to the those of the French study that randomized patients to IFN- alone or IFN- with ara-C. In the French study, the CHR rate was significantly higher with the combination (P = .003), as was the incidence of major cytogenetic response at 12 months (41% v 24%, P < .001). As in previous studies,5-9,22 the landmark analysis confirmed again the importance of achieving minimal tumor burden for improved survival (Fig 3).
With the present follow-up time, the estimated 4-year survival rate of 70% (Fig 1) is similar to that achieved with IFN- with or without low-dose ara-C (Fig 4). This is in contrast to the study by Guilhot et al,22 in which the addition of low-dose ara-C was associated with significantly longer survival. The difference in our study may be due to different population characteristics, the number of patients enrolled onto the study, the follow-up time, or the design of our study (sequential single-arm trials) and treatment schedule. In our study, patients treated with IFN- without ara-C had a better survival rate than the same patient group in the French study (3-year survival rate, 83% and 79%, respectively). The French study22 had a larger number of patients treated in a randomized approach and would therefore be more reliable in the estimation of outcome and detection of relatively small differences in survival (3-year survival rate, 86% v 79%; P = .02). Future trials comparing IFN- alone with IFN- plus low-dose ara-C will further define the benefit of additional ara-C therapy.
Similar favorable results were reported by others with the combination of IFN- and ara-C22-25 (Table 6). Most studies, including this one, have shown an independent association between achieving minimal tumor burden (CHR, cytogenetic response) and survival prolongation. In this analysis, the outcome with CHR at 12 months was closer to the outcome with minor cytogenetic response (Fig 3), either because of the additional benefit with low-dose ara-C (suppression of Ph and suppression of evolved or resistant clones without an effect on Ph suppression) or the small numbers and follow-up time.
The positive results with IFN- plus low-dose ara-C have been accomplished with acceptable side effects and with a lower dose schedule of IFN- compared with our previous schedules (3.7 megaunits/m2 v 5 megaunits/m2 median IFN- dose). These results are in line with investigational aims to improve suppression of Ph-positive disease and to reduce costs and side effects.
Our studies have consistently shown a higher incidence of CHR, a higher incidence of cytogenetic response, and higher survival rates than other series. This may be due to different population characteristics and risk groups as well as to differences in the IFN- dose schedules delivered.37,38 The proportions of patients in our series with good-, intermediate-, and poor-risk disease were about 53%, 33%, and 14%, respectively, compared with 25% to 40%, 30% to 35%, and 30% to 45%, respectively, in other studies.6-8,16 However, when patients were evaluated within risk groups (Table 5), the CHR and cytogenetic response rates were still significantly higher than in other studies, even among poorer-risk patients. It is also encouraging that the more recent combination studies have reported results similar to ours, particularly studies using the maximum-tolerated dose of IFN- (Table 6). It is also possible that the maximum-tolerated IFN- dose may be lower and less critical for achieving significant degrees of cytogenetic response when combined with low-dose ara-C.
Prognostic models have remained useful in the identification of different risk groups for response to IFN- therapy and for survival and in assessing whether there are differences in outcome in different series using similar therapies. This study demonstrates a good segregation of patient response by risk group and a difference in survival by response but not by risk group. A possible intriguing explanation is that cytogenetic response (occurring in a larger percentage of patients) now overrides risk group as a more important determinant of long-term prognosis in CML.
In summary, the results of IFN- plus daily low-dose ara-C combination therapy in patients with Ph-positive early chronic-phase CML were promising. Future studies will attempt to combine them simultaneously or in sequence with other successful approaches, such as homoharringtonine, intensive chemotherapy, autologous stem-cell transplantation, and immunomodulatory strategies, to improve the incidence, quality, and duration of complete and major cytogenetic responses. It is hoped that this will produce prolonged event-free survival in a proportion of patients with Ph-positive CML.
|
REFERENCES
|
|---|
1.
Kantarjian H, Deisseroth A, Kurzrock R, et al: Chronic myelogenous leukemia: A concise update. Blood 82:691-703, 1993[Free Full Text]
2.
Goldman J, Szydlo R, Horowitz M, et al: Choice of pretransplant treatment and timing of transplants or chronic myelogenous leukemia in chronic phase. Blood 82:2235-2238, 1993[Abstract/Free Full Text]
3.
Clift R, Appelbaum F, Thomas E: Bone marrow transplantation for chronic myelogenous leukemia. Blood 83:2752-2743, 1994[Free Full Text]
4.
Ozer H, George S, Schiffer C, et al: Prolonged subcutaneous administration of recombinant alpha 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: Effect on remission duration and survival. Cancer and Leukemia Group B Study 8686. Blood 82:2975-2984, 1993[Abstract/Free Full Text]
5.
Kantarjian H, Smith T, O'Brien Set al: Prolonged survival in chronic myelogenous leukemia following cytogenetic response to alpha interferon therapy. Ann Intern Med 122:254-261, 1995[Abstract/Free Full Text]
6.
Tura S, Baccarani M, Zuffa E for the Italian Cooperative Study Group on Chronic Myeloid Leukemia: Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med 330:820-825, 1994[Abstract/Free Full Text]
7.
Hehlmann R, Heimpel H, Hasford J, et al: Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. Blood 84:4064-4077, 1994[Abstract/Free Full Text]
8.
Allan N, Richards S, Shepard P, et al: UK-Medical Research Council randomized, multicenter trial of interferon-alpha n 1 for chronic myeloid leukemia: Improved survival irrespective of cytogenetic response. Lancet 345:1392-1397, 1995[Medline]
9.
Ohnishi K, Ohno R, Tomonaga M, et al: A randomized trial comparing interferon-alpha with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase. Blood 86:906-916, 1995[Abstract/Free Full Text]
10.
Daley GQ, Van Etten RA, Baltimore D: Induction of chronic myelogenous leukemia in mice by the P210BCR/ABL gene of the Philadelphia chromosome. Science 247:824-830, 1990[Abstract/Free Full Text]
11.
Elefanty AG, Hariharan IK, Cory S: bcr-abl, the hallmark of chronic myeloid leukemia in man, induces multiple hematopoietic neoplasms in mice. EMBO J 9:1069-1078, 1990[Medline]
12.
Kelliher MA, McLaughlin J, Witte ON, et al: Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and bcr/abl. Proc Natl Acad Sci USA 87:6649-6653, 1990[Abstract/Free Full Text]
13.
Heisterkamp N, Jenster G, ten Hoeve Jet al: Acute leukemia in bcr/abl transgenic mice. Nature 344:251-253, 1990[Medline]
14.
Mahon F, Montastruc M, Faberes C, et al: Predicting complete cytogenetic response in chronic myelogenous leukemia patients treated with recombinant interferon-alpha. Blood 84:3592, 1994[Free Full Text]
15.
Hasford J, Baccarani M, Hehlmann R, et al: Interferon-alpha hydroxyurea in early chronic myeloid leukemia: A comparative analysis of the Italian and German chronic myeloid leukemia trials with interferon-alpha. Blood 87:5384-5391, 1996[Abstract/Free Full Text]
16.
Kantarjian HM, O'Brien S Anderlini P, et al: Treatment of chronic myelogenous leukemia: Current status and investigational options. Blood 87:3069-3081, 1996[Free Full Text]
17.
Chronic Myeloid Leukemia Trialists' Collaborative Group. Interferon alfa versus chemotherapy for chronic myeloid leukemia: A meta-analysis of seven randomized trials. J Natl Cancer Inst 89:1616-1620, 1997[Abstract/Free Full Text]
18.
Sokal J, Leong S, Gomez G: Preferential inhibition by cytarabine of CFU-GM from patients with chronic granulocytic leukemia. Cancer 59:197-202, 1987[Medline]
19.
Sokal J, Beingner SH: Low-dose cytosine arabinoside by subcutaneous infusion in early and advanced chronic granulocytic leukemia. Blood 68:233a, 1986 (abstr)
20.
Robertson MJ, Tantravahi R, Griffin JD, et al: Hematologic remission and cytogenetic improvement after treatment of stable-phase chronic myelogenous leukemia with continuous infusion of low-dose cytarabine. Am J Hematol 43:95-102, 1993[Medline]
21.
Kantarjian H, Keating M, Estey E, et al: Treatment of advanced Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-alpha and low-dose cytarabine. J Clin Oncol 10:772-778, 1992[Abstract/Free Full Text]
22.
Guilhot F, Chastang C, Michallet M, et al: Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med 337:223-229, 1997[Abstract/Free Full Text]
23.
Silver R, Szatrowski T, Peterson B, et al: Combined a-interferon and low dose cytosine arabinoside for Ph+ chronic phase myeloid leukemia. Blood 88:638a 1996 (suppl 1)
24.
Arthur CK, Ma DFF: Combined interferon alpha-2a and cytosine arabinoside as first-line treatment for chronic myeloid leukemia. Acta Haematol 89:15-21, 1993 (suppl 1)
25.
Thaler J, Hilbe W, Apfelbeck U, et al: Interferon-alpha-2c and low-dose ara-C for the treatment of patients with CML: Results of the Austrian multi-center phase II study. Leuk Res 21:75, 1997[Medline]
26.
Kantarjian HM, Vellekoop L, McCredie KB, et al: Intensive combination chemotherapy (ROAP) and splenectomy in the management of chronic myelogenous leukemia. J Clin Oncol 3:192-200, 1985[Abstract]
27.
Kantarjian HM, Talpaz M, Keating MJ, et al: Intensive chemotherapy induction followed by interferon-alpha maintenance in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Cancer 68:1201-1207, 1991[Medline]
28.
Cunningham I, Gee T, Dowling M, et al: Results of treatment of Ph' + chronic myelogenous leukemia with an intensive treatment regimen (L-5 protocol). Blood 53:375-396, 1979[Abstract/Free Full Text]
29.
Kantarjian HM, Dixon D, Keating MJ, et al: Characteristics of accelerated disease in chronic myelogenous leukemia. Cancer 61:1441-1446, 1988[Medline]
30.
Majlis A, Smith TL, Talpaz M, et al: Significance of cytogenetic clonal evolution in chronic myelogenous leukemia. J Clin Oncol 14:196-203, 1996[Abstract]
31.
Trujillo JM, Cork A, Ahearn MJ, et al: Hematologic and cytologic characterization of 8;21 translocation acute granulocytic leukemia. Blood 53:695-706, 1979[Abstract/Free Full Text]
32.
O'Brien S Kantarjian H, Feldman E, et al: Sequential homoharringtonine and interferon produce high hematologic and cytogenetic response rates in Philadelphia chromosome positive chronic myelogenous leukemia. Proc Am Soc Clin Oncol 14:336, 1995 (abstr)
33.
National Cancer Institute: Guidelines for Reporting of Adverse Drug Reactions. Bethesda, MD, Division of Cancer Treatment, National Cancer Institute, 1988
34.
Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958
35.
Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline]
36.
Kantarjian HM, Keating MJ, Smith TJ, et al: Proposal for a simple synthesis prognostic staging system in chronic myelogenous leukemia. Am J Med 88:1-8, 1990[Medline]
37.
Freund M, von Wussow P, Diedrich H, et al: Recombinant human interferon (IFN) alpha-2b in chronic myelogenous leukemia: Dose dependency of response and frequency of neutralizing anti-interferon antibodies. Br J Hematol 72:350-356, 1989[Medline]
38.
Alimena G, Morra E, Lazzarino M, et al: Interferon alpha-2b as therapy for Ph-positive chronic myelogenous leukemia: A study of 82 patients treated with intermittent or daily administration. Blood 72:642-647, 1989[Abstract/Free Full Text]
Submitted June 4, 1998;
accepted September 1, 1998.
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Facebook  Reddit  Technorati  Twitter What's this?
This article has been cited by other articles:
|
|
|
|
 
D. P. Steensma and R. E. Richard
Myeloproliferative disorders
ASH Self-Assessment Program,
January 1, 2007;
2007(1):
172 - 227.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. M. Kantarjian, M. Talpaz, S. O'Brien, D. Jones, F. Giles, G. Garcia-Manero, S. Faderl, F. Ravandi, M. B. Rios, J. Shan, et al.
Survival benefit with imatinib mesylate versus interferon-{alpha}-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia
Blood,
September 15, 2006;
108(6):
1835 - 1840.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Quintas-Cardama and J. E. Cortes
Chronic Myeloid Leukemia: Diagnosis and Treatment
Mayo Clin. Proc.,
July 1, 2006;
81(7):
973 - 988.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P. Radich, H. Dai, M. Mao, V. Oehler, J. Schelter, B. Druker, C. Sawyers, N. Shah, W. Stock, C. L. Willman, et al.
Gene expression changes associated with progression and response in chronic myeloid leukemia
PNAS,
February 21, 2006;
103(8):
2794 - 2799.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Talpaz, A. Rakhit, K. Rittweger, S. O'Brien, J. Cortes, S. Fettner, L. Hooftman, and H. Kantarjian
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.,
September 1, 2005;
11(17):
6247 - 6255.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Mollee, C. Arthur, T. Hughes, H. Januszewicz, A. Grigg, K. Bradstock, M. Wolf, J. Gibson, A. P. Schwarer, A. Spencer, et al.
Interferon-{alpha}-2b and oral cytarabine ocfosfate for newly diagnosed chronic myeloid leukaemia
Ann. Onc.,
December 1, 2004;
15(12):
1810 - 1815.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. M. Kantarjian, J. E. Cortes, S. O'Brien, R. Luthra, F. Giles, S. Verstovsek, S. Faderl, D. Thomas, G. Garcia-Manero, M. B. Rios, et al.
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,
October 1, 2004;
104(7):
1979 - 1988.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Kantarjian, M. Talpaz, S. O'Brien, G. Garcia-Manero, S. Verstovsek, F. Giles, M. B. Rios, J. Shan, L. Letvak, D. Thomas, et al.
High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia
Blood,
April 15, 2004;
103(8):
2873 - 2878.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P. Radich, T. Gooley, W. Bensinger, T. Chauncey, R. Clift, M. Flowers, P. Martin, J. Slattery, D. Sultan, and F. R. Appelbaum
HLA-matched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen
Blood,
July 1, 2003;
102(1):
31 - 35.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Cortes, F. Giles, S. O'Brien, D. Thomas, G. Garcia-Manero, M. B. Rios, S. Faderl, S. Verstovsek, A. Ferrajoli, E. J. Freireich, et al.
Result of high-dose imatinib mesylate in patients with Philadelphia chromosome--positive chronic myeloid leukemia after failure of interferon-{alpha}
Blood,
July 1, 2003;
102(1):
83 - 86.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. E. Cortes, M. Talpaz, F. Giles, S. O'Brien, M. B. Rios, J. Shan, G. Garcia-Manero, S. Faderl, D. A. Thomas, W. Wierda, et al.
Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy
Blood,
May 15, 2003;
101(10):
3794 - 3800.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. M. Kantarjian, J. E. Cortes, S. O'Brien, F. Giles, G. Garcia-Manero, S. Faderl, D. Thomas, S. Jeha, M. B. Rios, L. Letvak, et al.
Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses
Blood,
January 1, 2003;
101(1):
97 - 100.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. M. Kantarjian, M. Talpaz, S. O'Brien, T. L. Smith, F. J. Giles, S. Faderl, D. A. Thomas, G. Garcia-Manero, J.-P. J. Issa, M. Andreeff, et al.
Imatinib Mesylate for Philadelphia Chromosome-positive, Chronic-Phase Myeloid Leukemia after Failure of Interferon-{alpha}: Follow-Up Results
Clin. Cancer Res.,
July 1, 2002;
8(7):
2177 - 2187.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W.-I. Lee, H. Kantarjian, A. Glassman, M. Talpaz, and M.-S. Lee
Quantitative measurement of BCR/abl transcripts using real-time polymerase chain reaction
Ann. Onc.,
May 1, 2002;
13(5):
781 - 788.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Baccarani, G. Rosti, A. de Vivo, F. Bonifazi, D. Russo, G. Martinelli, N. Testoni, M. Amabile, M. Fiacchini, E. Montefusco, et al.
A randomized study of interferon-alpha versus interferon-alpha and low-dose arabinosyl cytosine in chronic myeloid leukemia
Blood,
March 1, 2002;
99(5):
1527 - 1535.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Kantarjian, C. Sawyers, A. Hochhaus, F. Guilhot, C. Schiffer, C. Gambacorti-Passerini, D. Niederwieser, D. Resta, R. Capdeville, U. Zoellner, et al.
Hematologic and Cytogenetic Responses to Imatinib Mesylate in Chronic Myelogenous Leukemia
N. Engl. J. Med.,
February 28, 2002;
346(9):
645 - 652.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Talpaz, S. O'Brien, E. Rose, S. Gupta, J. Shan, J. Cortes, F. J. Giles, S. Faderl, and H. M. Kantarjian
Phase 1 study of polyethylene glycol formulation of interferon {alpha}-2B (Schering 54031) in Philadelphia chromosome-positive chronic myelogenous leukemia
Blood,
September 15, 2001;
98(6):
1708 - 1713.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Jonasch and F. G. Haluska
Interferon in Oncological Practice: Review of Interferon Biology, Clinical Applications, and Toxicities
Oncologist,
February 1, 2001;
6(1):
34 - 55.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
B. J. Druker, C. L. Sawyers, R. Capdeville, J. M. Ford, M. Baccarani, and J. M. Goldman
Chronic Myelogenous Leukemia
Hematology,
January 1, 2001;
2001(1):
87 - 112.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. M. Kantarjian, M. Talpaz, T. L. Smith, J. Cortes, F. J. Giles, M. B. Rios, S. Mallard, J. Gajewski, A. Murgo, B. Cheson, et al.
Homoharringtonine and Low-Dose Cytarabine in the Management of Late Chronic-Phase Chronic Myelogenous Leukemia
J. Clin. Oncol.,
October 20, 2000;
18(20):
3513 - 3521.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Le Gouill, P. Talmant, N. Milpied, A. Daviet, M. Ancelot, P. Moreau, J.-L. Harousseau, R. Bataille, and H. Avet-Loiseau
Fluorescence In Situ Hybridization on Peripheral-Blood Specimens Is a Reliable Method to Evaluate Cytogenetic Response in Chronic Myeloid Leukemia
J. Clin. Oncol.,
April 7, 2000;
18(7):
1533 - 1538.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. L. Hensley, B. Peterson, R. T. Silver, R. A. Larson, C. A. Schiffer, and T. P. Szatrowski
Risk Factors for Severe Neuropsychiatric Toxicity in Patients Receiving Interferon Alfa-2b and Low-Dose Cytarabine for Chronic Myelogenous Leukemia: Analysis of Cancer and Leukemia Group B 9013
J. Clin. Oncol.,
March 13, 2000;
18(6):
1301 - 1308.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Kantarjian, J. V. Melo, S. Tura, S. Giralt, and M. Talpaz
Chronic Myelogenous Leukemia: Disease Biology and Current and Future Therapeutic Strategies
Hematology,
January 1, 2000;
2000(1):
90 - 109.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Faderl, M. Talpaz, Z. Estrov, and H. M. Kantarjian
Chronic Myelogenous Leukemia: Biology and Therapy
Ann Intern Med,
August 3, 1999;
131(3):
207 - 219.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
