Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase

BACKGROUND:

Imatinib mesylate given orally at a daily dose of 400 mg is the standard of care as initial therapy for patients with chronic myeloid leukemia (CML) in chronic phase (CML‐CP). Treatment guidelines propose dose escalation based on clinical assessments of disease response.

METHODS:

Response and survival were analyzed in a cohort of patients (n = 106) with newly diagnosed CML‐CP who were enrolled on the International Randomized Study of Interferon and STI571 (IRIS) trial, who began treatment with imatinib at a dose of 400 mg daily, and who subsequently underwent dose escalation to either 600 mg or 800 mg daily. Reasons for dose escalation were evaluated retrospectively based on 2 sets of criteria: the IRIS protocol‐defined criteria (n = 39 patients) and the European LeukemiaNet (ELN) recommendations (n = 48 patients).

RESULTS:

Among all 106 patients who underwent dose escalation, the rates of freedom from progression to accelerated phase or blast phase and overall survival were 89% and 84% at 3 years after dose increase, respectively. A cytogenetic response was obtained in 42% of patients who had their dose escalated based on protocol criteria and in 38% of patients who had their dose escalated according to the ELN recommendations.

CONCLUSIONS:

The results from this retrospective analysis supported imatinib dose escalation as an appropriate initial option for patients with CML‐CP who were experiencing suboptimal cytogenetic response or resistance. Cancer 2009. © 2008 American Cancer Society.     

Dasatinib or high‐dose imatinib for chronic‐phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily

BACKGROUND:

In patients with chronic‐phase chronic myeloid leukemia (CP‐CML), imatinib resistance is of increasing importance. Imatinib dose escalation was the main treatment option before dasatinib, which has 325‐fold more potent inhibition than imatinib against unmutated Bcr‐Abl in vitro. Data with a minimum of 2 years of follow‐up were available for the current study of dasatinib and high‐dose imatinib in CP‐CML resistant to imatinib at daily doses from 400 mg to 600 mg.

METHODS:

A phase 2, open‐label study was initiated of 150 patients with imatinib‐resistant CP‐CML who were randomized (2:1) to receive either dasatinib 70 mg twice daily (n = 101) or high‐dose imatinib 800 mg (400 mg twice daily; n = 49).

RESULTS:

At a minimum follow‐up of 2 years, dasatinib demonstrated higher rates of complete hematologic response (93% vs 82%; P = .034), major cytogenetic response (MCyR) (53% vs 33%; P = .017), and complete cytogenetic response (44% vs 18%; P = .0025). At 18 months, the MCyR was maintained in 90% of patients on the dasatinib arm and in 74% of patients on the high‐dose imatinib arm. Major molecular response rates also were more frequent with dasatinib than with high‐dose imatinib (29% vs 12%; P = .028). The estimated progression‐free survival also favored dasatinib (unstratified log‐rank test; P = .0012).

CONCLUSIONS:

After 2 years of follow‐up, dasatinib demonstrated durable responses and improved response and progression‐free survival rates relative to high‐dose imatinib. Cancer 2009. © 2009 American Cancer Society.     

Dynamics and management of cytopenias associated with dasatinib therapy in patients with chronic myeloid leukemia in chronic phase after imatinib failure

BACKGROUND:

The incidence, dynamics, and management of cytopenias were investigated in patients with chronic myeloid leukemia in chronic phase (CP CML) who received dasatinib therapy after imatinib failure.

METHODS:

Data were analyzed from 130 patients with CP CML who were treated with dasatinib from November 2003 to March 2006 in phase 1 (n = 22) or phase 2 or 3 (n = 108) studies for the development of grade 2 to 4 cytopenia (according to the National Cancer Institute Common Terminology Criteria [version 3.0]).

RESULTS:

Grade 2 to 4 neutropenia and/or thrombocytopenia occurred in 94 (72%) patients during dasatinib therapy and grade 3 to 4 occurred in 67 (52%) patients. Of the 94 patients who developed grade 2 to 4 neutropenia and/or thrombocytopenia, 64 (68%) also developed at least grade 2 anemia, and 16 (17%) developed grade 3 to 4 anemia. Management of cytopenias included transient dasatinib interruption in 35 (37%) patients, filgrastim in 12 (14%) patients, recombinant erythropoietin in 29 (45%) patients, and interleukin‐11 in 3 (5%) patients. Factors associated with an increased risk for developing grade 2 to 4 cytopenias were longer time from diagnosis to treatment, prior interferon or imatinib therapy, and a lower white blood cell count at the initiation of dasatinib therapy.

CONCLUSIONS:

Hematologic toxicity was frequent during dasatinib therapy in patients with CP CML, particularly at doses >100 mg daily. Treatment interruption and/or dose reduction as well as growth factor support were found to be safe and efficacious strategies to facilitate the continuous administration of dasatinib. Cancer 2009. © 2009 American Cancer Society.     

Dasatinib early intervention after cytogenetic or hematologic resistance to imatinib in patients with chronic myeloid leukemia

BACKGROUND:

Although many patients with chronic myeloid leukemia (CML) respond well to imatinib therapy, a significant proportion loses their initial response. Loss of response on imatinib is often because of BCR‐ABL mutations. Dasatinib is a 325‐fold more potent inhibitor of Bcr‐Abl than imatinib and has been associated with high rates of durable responses in patients with CML in chronic phase (CP) after imatinib failure.

METHODS:

To determine the optimal time for initiating dasatinib after loss of response on imatinib, data from dasatinib trials in CML‐CP were analyzed. Patients were grouped according to whether they received early intervention with dasatinib (ie, after cytogenetic recurrence on imatinib), rather than after both cytogenetic and hematologic recurrence.

RESULTS:

Overall, 72% of patients who received dasatinib after loss of a major cytogenetic response (MCyR) on imatinib achieved a complete cytogenetic response (CCyR) compared with 42% of patients who were treated after loss of both MCyR and complete hematologic response (CHR). Event‐free survival (EFS) also was higher after earlier dasatinib treatment (24‐month EFS rates: 89% after loss of MCyR on imatinib vs 29% after loss of both MCyR and CHR). Among patients who were treated after loss of CHR on imatinib with no prior MCyR, 26% achieved a CCyR with dasatinib, and the 24‐month EFS rate was 64%. In all 3 groups, CCyR rates were similar in patients with or without pre‐existing BCR‐ABL mutations.

CONCLUSIONS:

The results of the current study suggested that optimal outcomes are achieved when dasatinib is administered early after imatinib resistance. Cancer 2009. © 2009 American Cancer Society.     

伊马替尼治疗慢性粒细胞白血病患者在生育时中断药物治疗对胎儿和患者自身的影响

目的:分析伊马替尼治疗慢性粒细胞白血病（chronic myeloid leukemia,CML）患者在生育时中断药物治疗对胎儿和患者自身的影响。方法:回顾性分析本科室21例CML合并妊娠患者在接受伊马替尼治疗后的影响。结果:21名接受伊马替尼治疗的CML患者中有6名为意外怀孕,15名为计划怀孕。有生育意愿的女性患者需达到血液学或细胞学缓解至少两年,在受孕前1个月和孕期前3个月停服伊马替尼,男性患者则在生育前一个月停止接受伊马替尼的治疗。所有意外受孕的患者在孕期均未停止服用伊马替尼。21名患者共生产9名男婴和7名女婴（其中1名尿道下裂,1名轻度脑水肿）,其余有2名自然流产,3名选择性流产。结论:鼓励接受伊马替尼治疗的CML患者有计划的生育,对于治疗期间意外怀孕的患者,伊马替尼则会导致自然流产或先天性异常。     

Very long-term follow-up results of imatinib mesylate therapy in chronic phase chronic myeloid leukemia after failure of interferon alpha therapy

BACKGROUND:

The long‐term outcome of patients with chronic phase chronic myeloid leukemia treated with imatinib after failure of interferon alpha therapy has not been detailed.

METHODS:

In total, 368 patients were analyzed. Univariate and multivariate survival analyses were conducted using standard statistical methods.

RESULTS:

Overall, 247 patients (67%) achieved a complete cytogenetic response (CCyR). Of the 327 patients who were studied, 207 patients (63%) achieved a major molecular response (MMR), and 99 patients (30%) had undetectable breakpoint cluster region/c‐abl oncogene (BCR‐ABL) levels at some time during therapy. The estimated 10‐year survival rate was 68%, the progression‐free survival rate was 67%, and the event‐free survival rate was 51%. In multivariate analysis, age ≥60 years, hemoglobin <10 g/dL, bone marrow basophils ≥5%, any peripheral blasts, and clonal evolution were independent adverse factors for survival. The estimated 7‐year survival rate according to the presence of no factors (n = 154), 1 or 2 factors (n = 190), or ≥3 factors (n = 24) were 93%, 70%, and 25%, respectively (P < .01). Achieving an MMR, a CCyR, or a partial cytogenetic response at 12 months was associated with significantly better 10‐year survival rate in a landmark analysis (10‐year survival rate, 80%‐90%) compared with achieving a minor cytogenetic response or a complete hematologic response (10‐year survival rate, 55%‐65%) or another response (10‐year survival rate, 10%). In a landmark analysis that included imatinib response at 12 months, achieving a major cytogenetic response or better (hazard ratio, 0.12; P < .001) and achieving a complete hematologic response or a minor cytogenetic response (hazard ratio, 0.36; P = .003) were significant favorable prognostic factors.

CONCLUSIONS:

The current results indicated that the estimated 10‐year survival rate of 68% for patients with chronic myeloid leukemia who receive imatinib after failure on interferon has improved. Cancer 2012;118: 3116–22. © 2011 American Cancer Society.     

Significance of suboptimal response to imatinib,as defined by the European LeukemiaNet,in the long‐term outcome of patients with early chronic myeloid leukemia in chronic phase

BACKGROUND:

The European LeukemiaNet recommendations for chronic myeloid leukemia (CML) defined a group of patients with suboptimal response to imatinib. The significance of this response was not well defined.

METHODS:

The significance of having had a suboptimal response during imatinib therapy among 281 patients with CML treated with standard‐dose (n = 73) or high‐dose (n = 208) imatinib was investigated.

RESULTS:

Rates of suboptimal response at 6, 12, and 18 months were 4%, 8%, and 40%, respectively, and were not influenced by Sokal risk score. Patients with a suboptimal response at 6 months had a significantly lower probability of eventually achieving a complete cytogenetic response (CCyR) compared with those with an optimal response (30% vs 97%; P < .001), and their event‐free survival (EFS) and transformation‐free survival (TFS) were found to be similar to those with criteria for failure at this time point. Suboptimal response at 12 months defined a group with a similar TFS as those with optimal response, but with worse EFS. In contrast, patients with a suboptimal response at 18 months had outcomes that were similar to those patients with an optimal response. A multivariate analysis confirmed the significance of response category after adjusting for pretreatment characteristics and imatinib dose.

CONCLUSIONS:

The results of the current study suggested that suboptimal response was a heterogeneous category, and some patients had an outcome that mirrored that of patients with failed therapy. Interventions aimed at improving this outcome are required. Cancer 2009. © 2009 American Cancer Society.     

p21 Confers resistance to imatinib in human chronic myeloid leukemia cells

Imatinib is a Bcr-Abl inhibitor used as first-line therapy of chronic myeloid leukemia (CML). p21^Cip1, initially described as a cell cycle inhibitor, also protects from apoptosis in some models. We describe that imatinib down-regulates p21^Cip1 expression in CML cells. Using K562 cells with inducible p21 expression and transient transfections we found that p21 confers partial resistance to imatinib-induced apoptosis. This protection is not related to the G2-arrest provoked by p21, a decrease in the imatinib activity against Bcr-Abl or a cytoplasmic localization of p21. The results suggest an involvement of p21^Cip1 in the response to imatinib in CML.     

Cysteine‐rich protein 61 regulates the chemosensitivity of chronic myeloid leukemia to imatinib mesylate through the nuclear factor kappa B/Bcl‐2 pathway

Although the targeted tyrosine kinase inhibitor imatinib mesylate (IM) has achieved significant responses against CML in the clinical setting, a small proportion of patients fail to respond to IM treatment and their disease continues to progress, indicating resistance to IM therapy. As a secreted extracellular matrix protein, cysteine‐rich protein 61 (Cyr61) plays an important role in the resistance of solid tumors to chemotherapy, but its role in CML is unclear. In the present study, we observed that Cyr61 levels were upregulated in the plasma and bone marrow (BM) of patients with CML as well as in K562 cells. This upregulation of Cyr61 significantly decreased IM‐induced cellular apoptosis of K562 cells through nuclear factor kappa B/B‐cell lymphoma 2 pathways. Inhibition of Cyr61 restored the chemosensitivity of K562 cells to IM both in vitro and in vivo. Thus, our results showed for the first time that Cyr61 plays an important role in regulating the chemosensitivity of CML cells to IM, suggesting that selectively targeting Cyr61 directly or its relevant effector pathways may provide potential value in improving the clinical response of patients with CML to IM treatment.     

An approach to the management of chronic myeloid leukemia in British Columbia

Chronic myeloid leukemia (cml) is a myeloproliferative disorder whose therapy has changed dramatically since the late 1990s. With the introduction of the tyrosine kinase inhibitor (tki) imatinib mesylate, the treatment outcomes for patients with cml have improved markedly, and hematopoietic stem-cell transplantation is no longer routinely offered as first-line therapy for most patients in chronic phase.However, resistance to tki therapy is increasingly being recognized, and alternative therapy is needed for this group of patients. In addition, the development of models predicting response to tki therapy is desired, so that appropriate treatment strategies can be used for individual patients. The present report serves to outline the approach to the treatment of cml in British Columbia and to highlight areas of ongoing research.     

Treatment of chronic myeloid leukemia in the imatinib era: perspective from a developing country

BACKGROUND: There is paucity of data from developing countries on the efficacy and safety of imatinib mesylate in chronic myeloid leukemia (CML). The primary objective of this study was to document complete and partial cytogenetic responses to imatinib in all phases of CML. Secondary objectives included evaluations of complete hematologic response, safety, time to progression, and survival. METHODS: Two hundred seventy-five patients in all phases of CML who received treatment with imatinib from January 2001 to December 2005 were included in the study. All patients had on bone marrow or BCR-ABL positive in peripheral blood by polymerase chain reaction. RESULTS: After a median follow-up of 18 months, major cytogenetic responses (Ph <35%) in chronic phase (CP), accelerated phase (AP), and blastic phase (BP) were documented in 61%, 57%, and 28% of patients, respectively. A complete cytogenetic response was observed in 39.4%, 35.7%, and 14.3% of patients in CP, AP, and BP, respectively; and a complete hematologic response was observed in 90%, 86%, and 30%, respectively. The median time to progression at 18 months was 91% in CP and 68% in AP. The overall survivals in CP, AP, and BP at 18 months was 92%, 74%, and 38%, respectively. CONCLUSIONS: Impressive hematologic, cytogenetic, and molecular responses to imatinib were observed, similar to the responses reported in patients from Western countries. Patients had good compliance, toxicity was limited, and overall quality of life was improved markedly. The results indicated that the biology of CML is not different in patients from developing countries.     

Measuring response to BCR-ABL inhibitors in chronic myeloid leukemia

In patients with chronic myeloid leukemia (CML), the hallmark Philadelphia chromosome is the marker of disease that can be detected by conventional metaphase cytogenetics, fluorescence in situ hybridization, or polymerase chain reaction. The current "gold standard" of treatment response is cytogenetic response. Cytogenetic response to imatinib is strongly associated with disease progression and survival. Various strategies aimed at improving cytogenetic response have been explored, such as escalation of imatinib and switching to the newer breakpoint cluster region/v-abl Abelson murine leukemia viral oncogene (BCR-ABL) inhibitors dasatinib and nilotinib. Data from recent randomized trials of dasatinib and nilotinib as first-line therapy of newly diagnosed chronic-phase CML suggest that these agents are more effective than imatinib in achieving 6-month and 12-month complete cytogenetic responses. However, it is still too early to know whether or not this early response will translate into a long-term survival advantage. In addition, more sensitive assays to detect residual disease also may be associated with improved long-term outcomes. The deepest measure of response-a complete molecular response-may help identify patients who can stop taking imatinib for the short term, although the long-term consequences of this strategy remain unknown.     

Asparaginase induces apoptosis and cytoprotective autophagy in chronic myeloid leukemia cells

The antitumor enzyme asparaginase, which targets essential amino acid L-asparagine and catalyzes it to L-aspartic acid and ammonia, has been used for years in the treatment of acute lymphoblastic leukemia (ALL), subtypes of myeloid leukemia and T-cell lymphomas, whereas the anti-chronic myeloid leukemia (CML) effect of asparaginase and its underlying mechanism has not been completely elucidated. We have shown here that asparaginase induced significant growth inhibition and apoptosis in K562 and KU812 cells. Apart from induction of apoptosis, we reported for the first time that asparaginase induced autophagic response in K562 and KU812 cells as evidenced by the formation of autophagosome, microtubule-associated protein light chain 3 (LC3)-positive autophagy-like vacuoles, and the upregulation of LC3-II. Further study suggested that the Akt/mTOR (mammalian target of rapamycin) and Erk (extracellular signal-regulated kinase) signaling pathway were involved in asparaginase-induced autophagy in K562 cells. Moreover, blocking autophagy using pharmacological inhibitors {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, chloroquine (CQ) and quinacrine (QN) enhanced asparaginase-induced cell death and apoptosis, indicating the cytoprotective role of autophagy in asparaginase-treated K562 and KU812 cells. Together, these findings provide a rationale that combination of asparaginase anticancer activity and autophagic inhibition might be a promising new therapeutic strategy for CML.     

伊马替尼一线治疗慢性粒细胞白血病慢性期患者- 单中心十年回顾性分析*

目的：总结以伊马替尼为一线治疗的慢性粒细胞白血病（chroni cmyeloid leukemia,CML ）初治患者的疗效和生存。方法：回顾性分析南昌大学第一附属医院2003年1 月至2013年12月间收治的295 例CML 初治患者的临床资料,其中185 例为入组格列卫全球患者援助项目（GIPAP）行伊马替尼治疗、30例为干扰素（IFN-α）治疗、50例为羟基脲单药治疗和30例为异基因外周血造血干细胞移植（allogeneic hematopoietic stem cell transplantation ,Allo-HSCT）治疗的患者,分析各组患者的治疗疗效和生存情况。结果：伊马替尼治疗组和Allo-HSCT 治疗组患者完全血液学缓解率（complete hematologic remission ,CHR ）均为96.7% ,完全细胞遗传学缓解率（complete cytogenetic remission,CCyR）为89.7% 和93.3% ,完全分子学缓解率（complete molecular remission ,CMoR）为49.7% 和83.3%（P = 0.001）;而干扰素和羟基脲治疗组CHR 、CCyR和CMoR 均明显低于伊马替尼治疗组和Allo-HSCT 治疗组。伊马替尼组患者的总生存时间（overall survival,OS）明显优于其他组（P < 0.001）,甚至优于Allo-HSCT 治疗组（10年OS为89.0% vs .67.0% ,P < 0.001）。 Cox 多因素分析显示接受伊马替尼治疗（HR= 5.267,95%CI 为1.054～1.940,P = 0.022）和获得CCyR（HR= 9.541,95%CI 为1.692～10.513,P = 0.002）是影响本组患者预后良好的独立因素。结论：CML 初治患者接受伊马替尼治疗可以获得更高的CHR 和CCyR,且OS更优,伊马替尼适合作为中国初治CML 患者的一线治疗。