Result of high-dose imatinib mesylate in patients with Philadelphia chromosome—positive chronic myeloid leukemia after failure of interferon-α

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 83-86 ◽  
Author(s):  
Jorge Cortes ◽  
Francis Giles ◽  
Susan O'Brien ◽  
Deborah Thomas ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Rate ◽  
Interferon Α ◽  
High Dose ◽  
Molecular Remission

Abstract Imatinib at 400 mg daily is effective in chronic-phase chronic myeloid leukemia (CML) after interferon failure, although only a few patients achieve a molecular remission. We investigated whether higher doses of imatinib may be more effective. Thirty-six patients with chronic-phase CML after failure on interferon-α were treated with 400 mg imatinib twice daily. Median time from diagnosis was 25 months (range, 10-135 months); 4 patients (11%) had clonal evolution. All 11 patients with active disease achieved complete hematologic response. Excluding patients with fewer than 35% Ph-positive metaphases before the start of therapy, 19 (90%) of 21 evaluable patients achieved a major cytogenetic response. Of 27 evaluable patients, 24 (89%) achieved a complete cytogenetic response. Quantitative polymerase chain reaction was performed in bone marrow every 3 months. Of 32 evaluable patients, 18 (56%) showed BCR-ABL/ABL percentage ratios lower than 0.045%, including 13 (41%) with undetectable levels. With a median follow-up of 15 months, all patients were alive in chronic phase. Toxicities were similar to those reported with standard dose; 71% of patients continue to receive 600 mg or more of imatinib daily. In conclusion, high-dose imatinib induces complete cytogenetic responses in most patients with chronic-phase CML after interferon failure. This is accompanied by a high rate of molecular remission. (Blood. 2003;102:83-86)

Expression of interferon-α (IFN-α) receptor 2c at diagnosis is associated with cytogenetic response in IFN-α–treated chronic myeloid leukemia

Blood ◽  
2001 ◽  
Vol 97 (11) ◽  
pp. 3568-3573 ◽  
Author(s):  
Christophe Barthe ◽  
François-Xavier Mahon ◽  
Marie-José Gharbi ◽  
Carole Fabères ◽  
Chrystèle Bilhou-Nabéra ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Alternative Therapy ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
External Control ◽  
Interferon Α ◽  
Kaplan Meier ◽  
Complete Hematologic Response

For the management of chronic myeloid leukemia (CML), prediction or early determination of the response to interferon-alpha (IFN-α) treatment is important for identifying nonresponder patients to whom alternative therapy may be proposed. In this study, the levels of expression of both BCR-ABL and subunit 2c of IFN-α receptor (IFN-αR2c) genes were analyzed at diagnosis in 74 patients with chronic phase CML treated with an IFN-α monotherapy. By using blood samples, real-time quantitative polymerase chain reaction was performed to quantify BCR-ABL, IFN-αR2c, and G6PDH mRNA as external control. The results were compared with hematologic and cytogenetic responses to IFN-α. A wide variation in the BCR-ABL/G6PDH ratio was observed at diagnosis (median, 6.68%; range, 0.18%-41.31%), but no significant association with response to IFN-α was observed. In contrast, the variation of IFN-αR2c/G6PDH ratio at diagnosis was significantly associated with the achievement of major cytogenetic response (MCR; 34% or lower Ph+metaphases). Median values of IFN-αR2c/G6PDH ratio for patients achieving MCR and for those who did not achieve it were 110.75% (range, 9.47%-612.30%) and 64.42% (range, 5.96%-425.40%), respectively (P = .037). In addition, this novel molecular factor, combined with the achievement of complete hematologic response at 3 months, makes it possible to predict MCR achievement with high probability by Kaplan-Meier analysis (91% ± 17% at 24 months; P = .0001).

Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-α treatment

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1039-1043 ◽  
Author(s):  
Andreas Hochhaus ◽  
Brian Druker ◽  
Charles Sawyers ◽  
Francois Guilhot ◽  
Charles A. Schiffer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Interferon Α ◽  
Imatinib Treatment ◽  
Serious Adverse Events ◽  
Response Level

Abstract Imatinib mesylate, a targeted inhibitor of BCR-ABL tyrosine kinase, is the standard of care for chronic myeloid leukemia (CML). A phase 2 trial of imatinib in late chronic-phase (CP) CML after interferon-α (IFNα) failure enrolled 532 patients, 454 with a confirmed diagnosis of CP CML. Median time from diagnosis was 34 months; median duration of imatinib treatment was 65 months. Cumulative best rates of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) were 67% and 57%, respectively. At the 5-year landmark, 184 (41%) of the 454 patients are in CCyR. At more than 6 years, 199 (44%) of the 454 patients remain on imatinib. Most responses occurred within 12 months of starting imatinib; however, some patients achieved initial MCyR and CCyR more than 5 years after imatinib initiation. Estimated rates of freedom from progression to accelerated phase (AP) and blastic phase (BP) and overall survival at 6 years were 61% and 76%, respectively. Both freedom from progression to AP/BP and overall survival (OS) were associated with cytogenetic response level at 12 months. No increase in rates of serious adverse events was observed with continuous use of imatinib for up to 6.5 years, compared with earlier time points. Imatinib continues to be an effective and safe therapy for patients with CP CML after failure of IFN.

A randomized study of interferon-α versus interferon-α and low-dose arabinosyl cytosine in chronic myeloid leukemia

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1527-1535 ◽  
Author(s):  
Michele Baccarani ◽  
Gianantonio Rosti ◽  
Antonio de Vivo ◽  
Francesca Bonifazi ◽  
Domenico Russo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Response Rate ◽  
Randomized Study ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Interferon Α ◽  
Arabinosyl Cytosine

Interferon-α (IFN-α) has significantly prolonged survival in chronic myeloid leukemia (CML), but some patients do not respond and many responses are not durable. To improve the results, IFN-α has been combined with other treatments, but so far only the association with low-dose arabinosyl cytosine (LDAC) has been shown to increase the response rate and to prolong survival. Here are reported the results of a study of 538 Philadelphia chromosome–positive CML patients who were assigned at random to treatment with IFN-α2a alone or in combination with LDAC. The scheduled dose of IFN-α2a was 56IU/m2/d. The scheduled dose of AC was 40 mg/d for the first 10 days of each month of treatment. The efficacy endpoints were a complete hematologic response rate at 6 months (62% in the IFN-α–plus–LDAC arm versus 55% in the IFN-α arm; P = .11), major cytogenetic response (MCgR) rate at 24 months (28% versus 18%; P = .003), and overall survival (5-year survival, 68% versus 65%; P = .77). Treatment did not affect overall survival within different prognostic risk groups: low, intermediate, or high. Also the duration of MCgR was identical. The results of this study confirm the results of a similar French study only for the response rate, not for survival, suggesting that the relationship between cytogenetic response and survival may be extremely variable and that a meta-analysis of these and other studies of IFN-α versus IFN-α plus LDAC is required to settle the issue of the role of LDAC in the treatment of CML.

Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome–positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 97-100 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Jorge E. Cortes ◽  
Susan O'Brien ◽  
Francis Giles ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Interferon Α ◽  
Combination Regimens ◽  
Philadelphia Chromosome Positive

Abstract Fifty patients with Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) in early chronic phase received imatinib mesylate, 400 mg orally daily. After a median follow-up of 9 months, 49 patients (98%) achieved a complete hematologic response and 45 patients (90%) achieved a major cytogenetic response, complete in 36 patients (72%). Compared with similar patients who received interferon-α with or without hydroxyurea or other interferon-α combination regimens, those receiving imatinib mesylate had higher incidences of complete and major (Ph < 35%) cytogenetic responses at 3 months (34% and 74% versus 1%-4% and 9%-24%, respectively), 6 months (52% and 80% versus 3%-7% and 11%-28%, respectively), and 9 months (60% and 77% versus 5%-11% and 14%-30%, respectively; P < .001). Competitive quantitative polymerase chain reaction (QPCR) studies at 9 months showed a median QPCR value (ratio of BCR-ABL/ABL transcripts × 100) of 0.59% overall and of 0.24% (range, 0.001%-29.5%) for complete cytogenetic response.

The development of imatinib as a therapeutic agent for chronic myeloid leukemia

Blood ◽  
2005 ◽  
Vol 105 (7) ◽  
pp. 2640-2653 ◽  
Author(s):  
Michael Deininger ◽  
Elisabeth Buchdunger ◽  
Brian J. Druker
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Chronic Phase ◽  
Initial Response ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Interferon Α ◽  
Disease Mutations ◽  
Risk Of Disease

AbstractImatinib has revolutionized drug therapy of chronic myeloid leukemia (CML). Preclinical studies were promising but the results of clinical trials by far exceeded expectations. Responses in chronic phase are unprecedented, with rates of complete cytogenetic response (CCR) of more than 40% in patients after failure of interferon-α (IFN) and more than 80% in newly diagnosed patients, a level of efficacy that led to regulatory approval in record time. While most of these responses are stable, resistance to treatment after an initial response is common in more advanced phases of the disease. Mutations in the kinase domain (KD) of BCR-ABL that impair imatinib binding have been identified as the leading cause of resistance. Patients with CCR who achieve a profound reduction of BCR-ABL mRNA have a very low risk of disease progression. However, residual disease usually remains detectable with reverse transcription–polymerase chain reaction (RT-PCR), indicating that disease eradication may pose a significant challenge. The mechanisms underlying the persistence of minimal residual disease are unknown. In this manuscript, we review the preclinical and clinical development of imatinib for the therapy of CML, resistance and strategies that may help to eliminate resistant or residual leukemia.

Better Molecular Response (MR) to Imatinib (IM) in Early Chronic Phase (CP) Versus Late CP Chronic Myeloid Leukemia (CML) Patients (pts) in Complete Cytogenetic Response (CCR): A Comparison at 24 Months of 2 Clinical Trials of the GIMEMA Working Party on CML on Behalf of the GIMEMA Working Party on Chronic Myeloid Leukemia (GIMEMA-CML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1096-1096 ◽  
Author(s):  
Angela Poerio ◽  
Marilina Amabile ◽  
Ilaria Iacobucci ◽  
Simona Soverini ◽  
Sabrina Colarossi ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Nested Pcr ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Working Party ◽  
Cytogenetic Response ◽  
Interferon Α ◽  
Molecular Response ◽  
Front Line ◽  
Log Reduction

Abstract We sought to determine the differences in molecular response between early and late CP pts with CML who achieved a CCR after treatment with IM at the standard dose of 400mg/d. We studied 2 different cohorts of patients in CCR: 67/191 (35%) pts after α-Interferon (α-IFN) failure enrolled on the CML/002/STI571 protocol 53/76 (70%) pts treated front line with a combination of IM and pegilated IFN-α (PEG-IFN) enrolled on the CML/011/STI571 protocol Cytogenetic response was monitored on bone marrow (BM) metaphases and molecular response was assessed by real time RT-PCR (TaqMan) BM and peripheral blood (PB) samples, collected at baseline, 3, 6, 9 and 12 months during the first year, and every 6 months thereafter. Molecular response was expressed as the ratio between BCR/ABL and β2-microglobulin (β2-M) x100. The lowest level of detectability of the method was 10−5. Negative results (i.e. undetectable transcript) were confirmed by nested PCR performed 4 times (sensitivity 10−6). For the purpose of this analysis, a major molecular response (MMR) was defined as a BCR-ABL/β2M value <0.0001%, which turned out to be roughly equivalent to a 3-log reduction and a complete molecular response (CMR) was defined as negative (undetectable) BCR/ABL levels confirmed by nested PCR. We observed a progressive decrease of the amount of BCR/ABL transcript in pts who achieved a CCR. At 24 months the median reduction in BCR/ABL transcript level was: a 3-log reduction in late CP pts a 4-log reduction in early CP pts In the latter group of pts MR was assessed also at 36 months. So we observed that 36 months after the first dose of IM and PEG-IFN pts who were still in CCR had the median value of BCR/ABL transcript of 0.00001% both in BM and PB. Therefore all these pts achieved a MMR. However only 8/53 (4%) pts were in CMR (undetectable BCR/ABL at least once as assessed by nested PCR). We conclude that front-line treatment with IM results in a better quality MR (4-log reduction in BCR/ABL transcript levels in early CP pts, as against a 3-log reduction in late CP pts). Figure Figure

Chromosomal abnormalities in Philadelphia chromosome–negative metaphases appearing during imatinib mesylate therapy in patients with newly diagnosed chronic myeloid leukemia in chronic phase

Blood ◽  
2007 ◽  
Vol 110 (8) ◽  
pp. 2991-2995 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Lynne V. Abruzzo ◽  
Susan O'Brien ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Progressive Disease ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Young Patients ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Newly Diagnosed

Abstract The development of chromosomal abnormalities (CAs) in the Philadelphia chromosome (Ph)–negative metaphases during imatinib (IM) therapy in patients with newly diagnosed chronic myecloid leukemia (CML) has been reported only anecdotally. We assessed the frequency and significance of this phenomenon among 258 patients with newly diagnosed CML in chronic phase receiving IM. After a median follow-up of 37 months, 21 (9%) patients developed 23 CAs in Ph-negative cells; excluding −Y, this incidence was 5%. Sixteen (70%) of all CAs were observed in 2 or more metaphases. The median time from start of IM to the appearance of CAs was 18 months. The most common CAs were −Y and + 8 in 9 and 3 patients, respectively. CAs were less frequent in young patients (P = .02) and those treated with high-dose IM (P = .03). In all but 3 patients, CAs were transient and disappeared after a median of 5 months. One patient developed acute myeloid leukemia (associated with − 7). At last follow-up, 3 patients died from transplantation-related complications, myocardial infarction, and progressive disease and 2 lost cytogenetic response. CAs occur in Ph-negative cells in a small percentage of patients with newly diagnosed CML treated with IM. In rare instances, these could reflect the emergence of a new malignant clone.

High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome–positive chronic phase chronic myeloid leukemia

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 2873-2878 ◽  
Author(s):  
Hagop Kantarjian ◽  
Moshe Talpaz ◽  
Susan O'Brien ◽  
Guillermo Garcia-Manero ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Complete Cytogenetic Response

Abstract Imatinib mesylate (STI571) is effective in chronic phase chronic myelogenous leukemia (CML). However, most patients treated with 400 mg imatinib daily have variable levels of residual molecular disease. We treated 114 patients with newly diagnosed chronic phase CML with 400 mg imatinib twice daily. Overall, 109 patients (96%) had a major cytogenetic response (Philadelphia chromosome [Ph] < 35%), and 103 (90%) had a complete response (Ph 0%). With a median follow-up of 15 months, no patient has progressed to accelerated or blastic phase. The estimated 2-year survival rate was 94%. By quantitative polymerase chain reaction (QPCR) studies, 71 (63%) of 112 patients showed BCR-ABL/ABL percentage ratios decrease to less than 0.05%, and 31 (28%) to undetectable levels. Compared with standard-dose imatinib, high-dose imatinib was associated with significantly better complete cytogenetic response (P = .0005), major molecular response (QPRC < 0.05%; P = .00001), and complete molecular response (undetectable BCR-ABL; P = .001). High-dose imatinib was well tolerated but resulted in more frequent myelosuppression; 82% of patients continue to receive 600 mg or more of imatinib daily. In conclusion, high-dose imatinib induced higher rates of complete cytogenetic response and of molecular response in patients with newly diagnosed chronic phase CML. (Blood. 2004; 103:2873-2878)

Tolerability-Adapted Imatinib 800 mg/d Versus 400 mg/d Versus 400 mg/d Plus Interferon-α in Newly Diagnosed Chronic Myeloid Leukemia

2011 ◽  
Vol 29 (12) ◽  
pp. 1634-1642 ◽  
Author(s):  
Rüdiger Hehlmann ◽  
Michael Lauseker ◽  
Susanne Jung-Munkwitz ◽  
Armin Leitner ◽  
Martin C. Müller ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Interferon Α ◽  
High Dose ◽  
Newly Diagnosed ◽  
Good Tolerability ◽  
International Scale ◽  
Dose Adaptation

Purpose Treatment of chronic-phase (CP) chronic myeloid leukemia (CML) with imatinib 400 mg/d can be unsatisfactory. Optimization of treatment is warranted. Patients and Methods In all, 1,014 newly diagnosed CP-CML patients were randomly assigned to imatinib 800 mg/d (n = 338), imatinib 400 mg/d (n = 325), or imatinib 400 mg/d plus interferon alfa (IFN-α; n = 351). Dose adaptation to avoid higher-grade toxicity was recommended. First primary end point was major molecular remission (MMR) at 12 months. Results A higher rate of MMR at 12 months occurred with tolerability-adapted imatinib 800 mg/d than with imatinib 400 mg/d (59% [95% CI, 53% to 65%] v 44% [95% CI, 37% to 50%]; P < .001) or imatinib 400 mg/d plus IFN-α (59% v 46% [95% CI, 40% to 52%]; P = .002). Median dose in the 800-mg/d arm was 628 mg/d with a maximum dose of 737 mg/d during months 4 to 6 and a maintenance dose of 600 mg/d. All three treatment approaches were well tolerated with similar grade 3 and 4 adverse events. Independent of treatment approach, MMR at 12 months showed better progression-free survival (99% v 94%; P = .0023) and overall survival (99% v 93%; P = .0011) at 3 years when compared with > 1% on the international scale or no MMR but showed no difference in 0.1% to < 1% on the international scale, which closely correlates with complete cytogenetic remission. Conclusion Treatment of early-phase CML with imatinib can be optimized. Early high-dose therapy followed by rapid adaptation to good tolerability increases the rate of MMR at 12 months. Achievement of MMR by month 12 is directly associated with improved survival.

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