Usefulness of low-dose and long-term administration of imatinib in patients with liver metastases of rectal GIST and GIST of stomach

Imatinib is an effective drug for KIT positive GIST, and the usual dose is 400 mg/day. On the other hand, imatinib sometimes causes leucopenia and it is hard to maintain a dosage of 400 mg/day. We reported here the two cases with a remarkable response of unresectable GIST using a low-dose and long-term administration of imatinib. It seems that a low dose and long-term administration of imatinib will be an important therapy for unresectable GIST.     

Medical treatment for gastrointestinal stromal tumor (GIST) in Japan

To facilitate an optimal diagnosis and treatment of GIST in Japan, the Japanese Clinical Practice Guideline for GIST was proposed by the GIST Guideline Subcommittee. Multidisciplinary treatment planning is needed(involving pathologists, radiologists, surgeons and medical oncologists)for patients with GIST. Medical treatment is usually selected for unresectable GIST, metastatic GIST at the initial examination, and recurrent GIST. Imatinib is strongly recommended for patients with KIT-positive GIST; the standard dose of imatinib mesylate(Glivec)is 400 mg/day. For patients with imatinib-resistant GIST, Sunitinib (Sutent)is now approved in Japan and is covered by medical insurance. However, high-dose imatinib(>400mg/day)has not yet been approved in Japan.     

Management of imatinib-associated skin rash in a patient with metastatic gastrointestinal stromal tumor: a case report

Purpose

Long-term continuous imatinib is recommended for adult patients with unresectable and/or metastatic KIT+ gastrointestinal stromal tumors (GIST) as long as the patient continues to benefit. In the adjuvant setting, recent findings indicate that patients at considerable risk of recurrence should receive at least 3 years of imatinib. Because imatinib is often administered for prolonged periods, proper management of imatinib-associated adverse events is crucial.

Case report

We report a 56-year-old man with metastatic KIT+ GIST of the liver who had Grade 3 imatinib intolerance (skin rash) when treatment was started. The rash was managed with antihistamine treatment (Dexchlorpheniramine maleate 4 mg per day) and several temporary (up to 2 weeks) dose interruptions. The patient’s skin rash partially improved, and he tolerated gradual reintroduction of imatinib over several months. The patient maintained imatinib 400 mg/d, and tolerated it during the 2 years when he was on antihistamine treatment. After 2 years, the patient continued imatinib therapy without having to take antihistamines. The patient responded according to RECIST 1.1 and Choi to imatinib treatment for his metastatic GIST (partial response). As of September, 2012, the patient has been on imatinib therapy for 131 months and remains progression free.

Conclusions

The results of this case report demonstrated that a patient with metastatic KIT+ GIST who was initially intolerant to imatinib maintained, and responded to imatinib therapy after treatment of an imatinib-associated adverse effect. These results suggest that initial intolerance to imatinib should not necessarily result in treatment discontinuation, as these adverse effects, when managed properly, may be tolerated and may decrease over time.

     

Optimizing the dose of imatinib for treatment of gastrointestinal stromal tumours: lessons from the phase 3 trials

Imatinib therapy for unresectable or metastatic gastrointestinal stromal tumour (GIST) is typically initiated at a dosage of 400mg/d. Two phase 3 studies investigated whether the higher dose of 800 mg/d - administered initially or upon progression on the 400-mg dose - would improve outcomes. Both the studies confirmed the 400mg/d starting dose for most patients. However, two groups benefited from the treatment with 800 mg/d of imatinib: patients with disease progression on standard-dose therapy, and patients whose tumour harbours an exon 9 mutation in KIT. Initial treatment with 800 mg/d of imatinib (400mg BID) should be considered for patients with KIT exon 9-mutant GIST. In unselected patients, dose optimisation to 800 mg/d may be warranted as a first step in managing progressive disease; such patients should be closely monitored.     

Long-term efficacy of imatinib for treatment of metastatic GIST

Purpose

Imatinib is an effective and approved treatment for advanced gastrointestinal stromal tumor (GIST). Continuous imatinib treatment is recommended by current guidelines. This review summarizes the long-term efficacy and safety of imatinib for patients with metastatic GIST.

Methods

Key clinical studies were reviewed—including B2222, S0033, and BFR14—with particular emphasis on recently reported results of the long-term clinical outcome of imatinib for metastatic GIST.

Results

The B2222 and S0033 studies recently reported 10-year follow-up results that demonstrate the long-term efficacy of imatinib. Furthermore, results from the BFR14 study demonstrate that imatinib treatment should not be interrupted and that the efficacy of imatinib following reintroduction is inferior compared with the continuous administration group. The S0033 study also supports the importance of dose optimization and dose escalation of imatinib in patients with KIT exon 9 mutations or progressive disease. These studies demonstrate that individual patient characteristics should be evaluated for optimal patient management. Managing adverse events proactively is very important to maintain compliance.

Conclusions

The results from these studies demonstrate that long-term imatinib extends survival in patients with advanced GIST. Furthermore, these studies support the safety of long-term imatinib therapy in this patient population.     

Systematic Review of Escalated Imatinib Doses Compared with Sunitinib or Best Supportive Care,for the Treatment of People with Unresectable/Metastatic Gastrointestinal Stromal Tumours Whose Disease has Progressed on the Standard Imatinib Dose

Introduction  

We conducted a systematic review of evidence on the effectiveness of imatinib at escalated doses of 600 mg/day or 800 mg/day for treatment of adults with unresectable or metastatic gastrointestinal stromal tumours (GIST), following progression on imatinib at the 400 mg/day dose, compared with sunitinib and/or ‘best supportive care’.     

Dose optimization of tyrosine kinase inhibitors to improve outcomes in GIST

Tyrosine kinase inhibitors such as imatinib and sunitinib have greatly improved clinical outcomes for patients with gastrointestinal stromal tumors (GIST). Dose optimization of these agents is critical and involves multiple considerations, including ensuring a durable response, monitoring drug blood levels to confirm adequate dosing, deciding whether to use high‐dose imatinib or switch to second‐line sunitinib in the event of disease progression and appropriately managing treatment‐associated side effects. Imatinib is the standard first‐line therapy for unresectable or metastatic GIST and is also an option for the adjuvant treatment of resected disease. Despite the efficacy and safety of imatinib in patients with advanced GIST, some individuals develop primary or secondary resistance or intolerance to the drug. For patients with advanced disease, imatinib dose escalation to 800 mg/day is warranted in cases of disease progression on imatinib 400 mg/day. In addition, patients with documented KIT exon 9 mutations are likely to derive benefit from initial treatment with high‐dose imatinib to improve clinical outcomes. For patients who fail imatinib, sunitinib is an effective treatment option. However, the decision to use either high‐dose imatinib or sunitinib should be based on the underlying cause of failure on imatinib, KIT mutational status and on whether the patient is intolerant of or has developed a resistance to imatinib. In this article we review the existing literature supporting the use of imatinib and sunitinib in GIST to provide a current clinical perspective on how best to use these agents in the management of GIST to optimize patient outcomes.     

Current trends in the management of malignant pleural mesothelioma

The European Society for Medical Oncology (ESMO) recommendations on the management of gastrointestinal stromal tumor (GIST) have recently been updated. Imatinib 400 mg/day remains the standard first-line treatment for patients with metastatic GIST. Mutational analysis has received a strong recommendation for diagnostic purposes. Furthermore, patients with KIT exon 9-activating mutations are now recommended to receive imatinib 800 mg/day as first-line treatment. Following progression during treatment with imatinib 400 mg/day, increasing the imatinib dose to 800 mg/day is advised. In the case of further progression or intolerance to imatinib, sunitinib 50 mg/day (schedule 4/2) is recommended. This article reviews the evidence underlying the updates to the ESMO recommendations on the management of GIST and discusses the implications of the changes.     

Adjuvant therapy with imatinib mesylate after resection of primary high-risk gastrointestinal stromal tumors in Japanese patients

Background

Imatinib mesylate, a small-molecule tyrosine kinase inhibitor, is currently used for adjuvant therapy of patients who have undergone resection of high-risk gastrointestinal stromal tumors (GISTs). There are no data concerning the efficacy and safety of postoperative adjuvant therapy with imatinib for Japanese or East Asian patients with GIST.

Methods

A single-arm, open-label, multicenter trial was conducted in 17 hospitals in Japan. The eligibility criteria included histologically proven primary high-risk GISTs with macroscopic complete resection. Patients were treated with imatinib at a dose of 400 mg/day for 1 year after surgery. The primary endpoint was recurrence-free survival as assessed by Kaplan–Meier analysis. The secondary endpoints were overall survival and safety. This study was registered with ClinicalTrials.gov, number NCT00171977.

Results

A total of 64 patients were enrolled between September 2004 and July 2006. The median age of the patients was 59.5 years. Forty-nine (76.6%) patients completed the 1-year treatment, whereas 15 (23.4%) patients did not complete the treatment owing to recurrence, toxicities, and consent withdrawal. At the median follow-up period of 109 weeks, 20 patients had recurrence. The 3-year recurrence rate was 42.7% (95% confidence interval 29.2–56.3%), which exceeded the expected recurrence rate in this trial. The recurrence-free and overall survival rates at 2 years were 71.1 and 93.7%, respectively. The most frequent adverse drug reaction of any grade was eyelid edema (48.4%), followed by neutropenia (40.6%), leukopenia (39.1%), nausea (39.1%), rash (37.5%), and peripheral edema (37.5%), most of which were mild and manageable.

Conclusions

Adjuvant therapy with imatinib at 400 mg/day for 1 year is well tolerated by Japanese patients and possibly reduces the risk of early recurrence of high-risk GISTs.     

Efficacy and safety profile of imatinib mesylate (ST1571) in Japanese patients with advanced gastrointestinal stromal tumors: a phase II study (STI571B1202)

BACKGROUND: Imatinib mesylate, an inhibitor of KIT, ABL protein, and platelet-derived growth factor receptor alpha (PDGFRalpha) tyrosine kinase, has recently been found to have a dramatic antitumor effect on gastrointestinal stromal tumor (GIST). The aim of this study was to assess the efficacy and safety of imatinib mesylate in Japanese patients with advanced GIST. METHODS: Patients with measurable lesions were enrolled between April 1, 2002, and September 20, 2002, using a design based on previous phase II studies in the United States and the European Union. The diagnosis of GIST was proven histologically with positive immunostaining for KIT (CD117). Imatinib mesylate was administered at a dose of either 400 mg or 600 mg once a day. Pharmacokinetic parameters and mutation analysis of c-kit were also assessed in a subgroup of patients. RESULTS: A total of 74 patients (28 receiving imatinib mesylate at 400 mg/day; 46 receiving 600 mg/day); median age, 56.0 years, were enrolled. No patient had a complete response, 51 patients (69%) had a partial response, and 19 patients (26%) had stable disease. The median progression-free survival time was 96 weeks. The estimated 3-year overall survival (Kaplan-Meier) rate for all patients was 73.6%. The most frequent adverse effects related to the drug were nausea (78%), diarrhea (70%), dermatitis (62%), facial edema (61%), edema of the lower limbs (58%), vomiting (54%), and eyelid edema (51%). Most of the adverse effects were mild and manageable. CONCLUSION: Imatinib mesylate is generally safe and has significant activity in the treatment of advanced GIST in Japanese patients.     

Management of Gastrointestinal Stromal Tumors: Looking Beyond the Knife. An Update on the Role of Adjuvant and Neoadjuvant Imatinib Therapy

Background

Gastrointestinal stromal tumors (GISTs) have traditionally been treated with surgical resection alone resulting in high rates of recurrence. However, the discovery of imatinib efficacy in GIST has revolutionized its management.

Discussion

Imatinib may be used as neoadjuvant therapy with the goal of reducing tumor size, minimizing surgical morbidity and, in some cases, rendering inoperable cases operable. In addition, imatinib use in the adjuvant setting to eradicate micrometastases and prevent recurrence has shown promising results in reducing relapse rates. Appropriate patient selection and optimal dose and duration of imatinib therapy remain undecided and require further investigation. We present a literature review and a case report of our patient with a symptomatic gastric GIST managed successfully utilizing neoadjuvant imatinib therapy, laparoscopic limited resection, and adjuvant imatinib therapy.     

A case of imatinib-resistant GIST treated by sunitinib

We report a case of imatinib-resistant GIST, successfully treated by sunitinib. A 62-year-old man with high-grade fever and a huge abdominal tumor was diagnosed with malignant GIST and multiple liver metastases. We performed total gastrectomy combined with distal pancreatectomy, and splenectomy for palliation. Imatinib at a dose of 300mg/day was administered postoperatively, and the liver metastases was well controlled. After nine months, abdominal dissemination increased, and we raised the dose of imatinib to 400mg/day for the progressive state. Subsequently, we had to discontinue imatinib due to its adverse effects. Because the tumors progressed greatly while imatinib was discontinued, we changed to sunitinib. After wards, tumors reduced and his general condition improved remarkably. Although tumors progressed after five months, he was able to obtain good QOL during the administration of sunitinib. Sunitinib is useful for imatinib-resistant GIST, and may be a promising treatment even for patients with poor PS.     

A phase I trial of imatinib in combination with mFOLFOX6–bevacizumab in patients with advanced colorectal cancer

Purpose

Platelet-derived growth factor receptor (PDGFR) inhibition by reducing tumoral interstitial fluid pressure might increase the efficacy of chemotherapy. Imatinib inhibits PDGFR kinase activity at therapeutically relevant doses. This phase I study aimed to assess the maximal tolerated dose (MTD) of imatinib in combination with mFOLFOX6–bevacizumab in patients with advanced colorectal cancer and to identify pharmacokinetic (PK) interactions and toxicities.

Methods

Eligible patients had measurable disease and adequate organ function. On day-14, patients commenced imatinib daily plus bevacizumab (5 mg/kg/2 weekly). Two weeks later (day 1), patients were also treated with full dose mFOLFOX6–bevacizumab for 12 cycles. Blood samples were taken for PK. DLTs defined in the first 6 weeks. Standard dose escalation of imatinib, with 3 patient cohorts: planned dose levels (DL): DL1; 400 mg, DL2; 600 mg, DL3; 800 mg daily.

Results

Ten patients enrolled. DL1 3 patients, DL2 7 patients. DLTs observed in 3 of 6 patients in DL2: febrile neutropenia (2); Grade 3 infection and Grade 4 neutropenia (1). Neutropenia was most frequent AEs: Grade 3/4 in >60 % of patients overall. In DL2 pts, imatinib clearance was reduced post-chemotherapy (P < 0.05). Oxaliplatin and 5FU PK unchanged by imatinib.

Conclusions

MTD was imatinib 400 mg plus full dose mFOLFOX–bevacizumab. Dose escalation of imatinib limited by neutropenia. Further study is warranted as imatinib can be delivered at levels that inhibit PDGFR.     

Systemic treatment of patients with gastrointestinal stromal tumor: Current status and future opportunities

Imatinib mesylate is considered the standard first-line systemic treatment for patients with advanced gastrointestinal stromal tumor (GIST). Results from recent research have expanded the knowledge of tyrosine kinase inhibitors in management of GIST. In the setting of unresectable and metastatic GIST, long-term follow-up of the B2222 study showed that imatinib 400 and 600 mg/d produced objective responses in 68% of patients and clinical benefit in 84%; it also extended median survival from 19 months in historical controls to 57 months. The MetaGIST analysis in two large phase 3 trials consisting of more than 1600 patients with metastatic and/or unresectable GIST showed that imatinib 800 mg/d compared with the standard 400-mg/d dose conferred a progression-free survival advantage in patients with KIT exon 9 mutations but not in other subpopulations. The higher starting dose does not significantly improve overall survival. The BFR14 trial demonstrated that interrupting imatinib is associated with a high risk of rapid disease progression. For patients with imatinib-intolerant or imatinib-resistant GIST, sunitinib or a variety of investigational agents, including the next-generation kinase inhibitor nilotinib, may be viable options for achieving disease control. In the setting of primary localized GIST, function- sparing surgical resection is the standard treatment approach, but some patients may be at substantial risk of disease recurrence and metastasis depending on tumor size, mitotic count, and possibly other factors. Initial results from ACOSOG Z9001 indicate that adjuvant imatinib for 1 year prolongs recurrence-free survival following surgical resection of larger (at least 3 cm) KIT-expressing GIST. Other ongoing studies are further exploring the role of imatinib in both adjuvant and neoadjuvant therapy. Recent updates to clinical practice guidelines and recommendations now incorporate some of these new findings.     

A phase I, first-in-human dose-escalation study of amuvatinib, a multi-targeted tyrosine kinase inhibitor, in patients with advanced solid tumors

Purpose

Amuvatinib is a novel orally administered tyrosine kinase inhibitor with in vitro pharmacological activity against mutant KIT, platelet-derived growth factor receptor alpha (PDGFRα), and Rad51. Amuvatinib was investigated in a first-in-human, single-agent, phase I, accelerated titration, dose-escalation trial (clinicaltrials.gov identifier: NCT00894894) in patients with solid tumors refractory to prior therapies or for which no standard therapy existed.

Methods

Twenty-two patients received amuvatinib dry powder capsules (DPC) from 100 to 1,500 mg daily in 28-day cycles. Safety, preliminary efficacy, pharmacologic activity, and pharmacokinetics were investigated.

Results

No dose-limiting toxicities were reported with amuvatinib DPC up to 1,500 mg/day, given as one or in divided doses, for 1–6 cycles. No maximum tolerated dose was reached. Five patients had serious adverse events, all unrelated to treatment. Exposure levels were low and variable. One gastrointestinal stromal tumor (GIST) patient who previously failed imatinib and sunitinib had a 2–[18F]fluoro-2-deoxyglucose positron emission tomography response and clinical stable disease. A second GIST patient had decreased Rad51 expression in a skin punch biopsy on days 15 and 29.

Conclusions

Amuvatinib shows in vitro inhibitory activity against multiple human tyrosine kinases including mutant KIT and PDGFRα and in vivo activity in human xenograft models in mice. Amuvatinib is also active as a DNA repair protein Rad51 inhibitor following chemotherapy. In this study, the amuvatinib DPC formulation was well tolerated up to 1,500 mg/day. While exposures were low and variable, a transient response in a refractory GIST patient warrants further investigation into single-agent amuvatinib in refractory GIST.     

Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors.

PURPOSE: Imatinib mesylate (Gleevec; Novartis, East Hanover, NJ)is a receptor tyrosine kinase inhibitor approved previously in 2001 by the United States Food and Drug Administration for the treatment of chronic myelogenous leukemia in blast crisis, accelerated phase, or in chronic phase after failure of IFN-alpha therapy. We review herein the clinical profile of this drug and the regulatory review leading to the approval of a supplemental New Drug Application for the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors (GISTs). Experimental Design: We discuss the efficacy and side effects of imatinib mesylate in a Phase II trial of 147 patients with metastatic and/or unresectable malignant GISTs, the basis for marketing approval, and postmarketing commitments by the drug's manufacturer. RESULTS: Imatinib was assessed in a single, open-label trial involving one European center and three centers in the United States. Seventy-three patients were randomly allocated to receive 400 mg of imatinib daily, and 74 patients received 600 mg daily. At the study report cutoff date, an objective response was confirmed in 56 patients; the overall response rate for the combined study arms was 38% (95% confidence interval, 30-46%). These responses were all partial responses. There was no statistically significant difference in response rates between the two dose groups. Adverse events included edema, fluid retention, nausea, vomiting, diarrhea, myalgias, skin rash, bone marrow suppression, bleeding, and elevations in aspartate aminotransferase, alanine aminotransferase, or bilirubin. Bleeding into the gastrointestinal tract or intratumoral sites occurred in 7 patients (5%) and was not correlated with thrombocytopenia or tumor bulk. The pharmacokinetics of imatinib in GIST patients were similar to those of chronic myelogenous leukemia patients. CONCLUSIONS: On February 1, 2001, imatinib mesylate was approved by the United States Food and Drug Administration for the treatment of malignant metastatic and/or unresectable GISTs. The recommended dose is 400 or 600 mg daily.     

甲磺酸伊马替尼治疗手术无法切除的晚期胃肠间质瘤

目的：探讨甲磺酸伊马替尼用于治疗晚期胃肠间质瘤的疗效及生存获益。方法：收集2004年9 月至2015年6 月天津医科大学肿瘤医院收治的无法手术切除的61例晚期胃肠间质瘤患者的临床资料,接受初始剂量400 mg/d 的口服甲磺酸伊马替尼治疗,定期随访,评价生存获益及药物不良反应。结果：61例患者开始接受治疗1 年后,治疗有效率为57.4%（35/ 61）,疾病控制率为88.5%（54/ 61）,Logic二元回归分析显示性别、年龄和腹盆腔多发病灶是影响治疗有效率的因素（P < 0.05）。 本组患者5 年累积生存率为53% ,Cox 回归模型分析提示腹盆腔的多发病灶是影响患者生存获益的重要因素（P < 0.05）。 除2 例患者出现出血,其余患者不良反应轻微。结论：甲磺酸伊马替尼显著改善晚期胃肠间质瘤的生存获益,可作为无法手术切除的晚期胃肠间质瘤的首选治疗。     

Treatment of advanced gastrointestinal stromal tumors in patients over 75 years old: clinical and pharmacological implications

Data about the patterns of care and the specific outcome of elderly patients with advanced gastrointestinal stromal tumors (GISTs) are almost nonexistent. Between 2001 and 2009, 44 patients ≥75 years old with advanced GISTs started first-line imatinib (400 mg/day) in seven participating institutions. Clinical data were collected by reviewing medical records and were entered in a comprehensive database. During the same period, 160 patients with advanced GIST (136 patients <75 years old, 24 patients ≥75 years old) had access to an imatinib blood level testing program. Imatinib plasma concentration (patient dose 400 mg/day) tests were centralized in a single laboratory. Median age was 78 years old (range 75–86). Thirty-six patients (82 %) experienced at least one adverse event (Table 2). Drug-related adverse events were mainly of grades 1 and 2 and were medically manageable. Permanent dose reduction (200–300 mg/day) was required for 20 patients (45.5 %) and was significantly more frequent for patients with performance status (PS) ≥2: 33.5 versus 8.5 %, p?=?0.04. Eight patients (18 %) required imatinib interruption for intolerance. Median PFS was 34.4 months (95 % CI 11.5–57.4) (Fig. 1). Median overall survival (OS) was 50.3 months (95 % CI 37–63.5). Performance status <2 was the sole pre-therapeutic factor associated with improved OS. No correlation was found between comorbidities and tolerance or outcome. Imatinib trough plasma concentrations increase with age, although this correlation did not reach statistical significance. First-line imatinib is a feasible and effective treatment in patients with advanced GISTs ≥75 years. Aging seems to have only a moderate impact on imatinib pharmacokinetics. Overall survival is similar to that of younger patients. Comorbidities did not result in increased incidence of toxicity. Careful follow-up regarding tolerance issues should be considered in elderly patients with poor PS.     

甲磺酸伊马替尼治疗不能切除和/或转移的胃肠道间质瘤的临床分析

目的：评价甲磺酸伊马替尼(ST1571)治疗不能手术切除和／或转移的胃肠道间质瘤疗效和毒性。方法：口服甲磺酸伊马替尼400mg/日治疗10例不能手术切除和／或转移的胃肠道间质瘤患者。结果：9例可评价疗效，4例部分缓解，4例稳定。10例评价不良反应，非血液学毒性有水肿(主要是眼眶周围水肿)、腹痛、腹泻、恶心呕吐、乏力、腹腔肿瘤出血、间歇性肌肉痉挛和结膜炎，大多为I～Ⅱ度。血液学毒性少见。结论：酪氨酸激酶抑制剂甲磺酸伊马替尼治疗不能手术切除和／或转移的胃肠道间质瘤有一定疗效，且毒性可耐受。     

Evaluation of Self-Reported Progression and Correlation of Imatinib Dose to Survival in Patients with Metastatic Gastrointestinal Stromal Tumors: An Open Cohort Study

Objectives

Self-reported progression was evaluated as a predictor of survival in patients with metastatic gastrointestinal stromal tumor (GIST).

Methods

This is a follow-up of an open cohort study of Life Raft Group (LRG) members with a diagnosis of KIT-positive metastatic GIST receiving imatinib from May 2000–December 2007 reporting their subjective response to therapy by completion of an internet-based questionnaire. Subjects received ≥?1 year of imatinib and reported an initial positive response. Members reporting stable disease or progression were excluded. Self-reported progression-free survival (srPFS) was compared with overall survival (OS) and analyzed by starting and last reported dose.

Results

One hundred sixty-nine subjects reported a mean starting dose of 527.8±177.9 mg/d at a mean age of 53.8±11.6 years at initial diagnosis. Of those reporting progression, 66% died versus 11% of those not reporting progression (P?<?0.0001). When analyzed by last reported dose, a median srPFS benefit of 27.3 months was observed for the >400 mg/d group (P?=?0.0017). Sixty-two percent of subjects who initiated therapy at >400 mg/d reported a dose reduction. When analyzed by last reported dose, a significant benefit in OS (P?=?0.0229) and srPFS (P?=?0.0069) was observed for subjects taking 600 over 400 mg/d.

Conclusions

srPFS strongly correlated with OS. Significant advantages were observed when last reported dose was considered, as was higher daily dose. These observations suggest that careful escalation to intermediate daily doses should be investigated further for its potential to reduce the incidence and severity of adverse events, but also as a strategy against developing secondary resistance to imatinib.