Showing papers by "Elias Jabbour published in 2011"
TL;DR: The maximum-tolerated dose (MTD) of barasertib is 1200 mg in patients with relapsed or newly diagnosed AML and treatment resulted in an overall hematologic response rate of 25%.
100 citations
TL;DR: Patients referred to tertiary care centers occasionally may have their diagnostic procedures repeated and have a final diagnosis that differs from that of the referring center, demonstrating the complexity of the diagnosis of MDS.
91 citations
TL;DR: Side effects that occur during treatment with imatinib, nilotinib or dasatinib—the currently approved TKI treatments for chronic myeloid leukemia—are described, including class effects and key differences in safety profiles.
Abstract: BCR-ABL-targeting tyrosine kinase inhibitors (TKIs) constitute the cornerstone of treatment for chronic myeloid leukemia. Although these agents are normally safe and effective, they can cause side effects that lead to intolerance and necessitate switching to an alternative treatment. In this review, we describe side effects that occur during treatment with imatinib, nilotinib or dasatinib-the currently approved TKI treatments for chronic myeloid leukemia-including class effects and key differences in safety profiles. We also describe how common side effects can be effectively managed and offer a working definition of intolerance that may be useful to clinicians when they consider switching between TKIs.
83 citations
TL;DR: Patients with poor performance status and no previous cytogenetic response to imatinib therapy have a low likelihood of responding to second-generation TKI with poor event-free survival and therefore should be offered additional treatment options.
77 citations
TL;DR: Clinical trial data from an evaluation of the response of specific mutant BCR‐ABL clones to TKIs is needed to establish the role of mutation testing in the management of CML, and comorbidities and drug safety profiles should be the basis for choosing a second‐line agent.
Abstract: Data demonstrating the superiority of nilotinib over imatinib in the frontline treatment of chronic myeloid leukemia (CML) and ongoing studies with dasatinib and bosutinib are rapidly changing the treatment landscape for CML. In this review, the authors discuss currently available therapies for CML, focusing on mechanisms of resistance to imatinib and treatment strategies to overcome resistance. Relevant articles were identified through searches of PubMed and abstracts from international hematology/oncology congresses. Additional information sources were identified from the bibliographies of these references and from the authors' own libraries and expertise. In vitro 50% inhibitory concentration (IC(50) ) data alone are not sufficient to guide the choice of a tyrosine kinase inhibitor (TKI) in the presence of a mutant breakpoint cluster region-v-abl Abelson murine leukemia viral oncogene homolog (BCR-ABL) clone, because there is a lack of data regarding how well such IC(50) values correlate with clinical response. A small subset of BCR-ABL mutant clones have been associated with impaired responses to second-generation TKIs (tyrosine to histidine mutation at codon 253 [Y253H], glutamic acid to lysine or valine mutation at codon 255 [E255K/V], and phenylalanine to cysteine or valine mutation at codon 359 [F359C/V] for nilotinib; valine to leucine mutation at codon 299 [V299L] and F317L for dasatinib); neither nilotinib nor dasatinib is active against the threonine to isoleucine mutation at codon 315 (T315I). For each second-generation TKI, the detection of 1 of a small subset of mutations at the time of resistance may be helpful in the selection of second-line therapy [corrected]. For the majority of patients, comorbidities and drug safety profiles should be the basis for choosing a second-line agent. Clinical trial data from an evaluation of the response of specific mutant BCR-ABL clones to TKIs is needed to establish the role of mutation testing in the management of CML.
76 citations
TL;DR: It is proposed that achievement ofCCyR and partial cytogenetic response at 3 months should be considered optimal and suboptimal responses, respectively, and the achievement of MMR offered no advantage over CCyR in defining long-term outcome in patients with newly diagnosed CML treated with second-generation TKIs.
Abstract: Purpose The response definitions proposed by the European LeukemiaNet (ELN) are defined on the basis of imatinib front-line therapy. It is unknown whether these definitions apply to patients treated with second-generation tyrosine kinase inhibitors (TKIs). Patients and Methods One hundred sixty-seven patients with newly diagnosed chronic myelogenous leukemia (CML) in chronic phase were treated with second-generation TKIs in phase II trials (nilotinib, 81; dasatinib, 86). Median follow-up was 33 months. Event-free survival (EFS) was measured from the start of treatment to the date of loss of complete hematologic response, loss of complete or major cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, progression to accelerated or blastic phases, or death at any time. Results Overall, 155 patients (93%) achieved complete cytogenetic response (CCyR), including 146 (87%) with major molecular response (MMR; complete in 46 patients [28%]). According to the ELN definitions, the rates...
75 citations
TL;DR: Hematopoietic stem cell transplantation is an important salvage option for TKI-resistant patients with or without BCR-ABL1 mutations, and patients with mutations were more likely to develop advanced disease and had worse outcomes after HSCT.
68 citations
TL;DR: A prognostic model specifically for patients with t-MDS that predicted overall survival and leukemia-free survival is devised and might facilitate the development of risk-adapted therapeutic strategies.
Abstract: Introduction/Background We evaluated the characteristics of a cohort of patients with myelodysplastic syndrome (MDS) related to therapy (t-MDS) to create a prognostic model. Patients and Methods We identified 281 patients with MDS who had received previous chemotherapy and/or radiotherapy for previous malignancy. Potential prognostic factors were determined using univariate and multivariate analyses. Results Multivariate Cox regression analysis identified 7 factors that independently predicted short survival in t-MDS: age ≥ 65 years (hazard ratio [HR], 1.63), Eastern Cooperative Oncology Group performance status 2-4 (HR, 1.86), poor cytogenetics (−7 and/or complex; HR, 2.47), World Health Organization MDS subtype (RARs or RAEB-1/2; HR, 1.92), hemoglobin ( 9 /dL; HR, 2.01), and transfusion dependency (HR, 1.59). These risk factors were used to create a prognostic model that segregated patients into 3 groups with distinct median overall survival: good (0-2 risk factors; 34 months), intermediate (3-4 risk factors; 12 months), and poor (5-7 risk factors; 5 months) ( P P = .003). This model also identified distinct survival groups according to t-MDS therapy. Conclusion In summary, we devised a prognostic model specifically for patients with t-MDS that predicted overall survival and leukemia-free survival. This model might facilitate the development of risk-adapted therapeutic strategies.
57 citations
TL;DR: Second-generation TKIs have the potential to replace imatinib as the standard of care for patients with early CML-CP and future CML therapy might include earlier use of these agents to help more patients achieve complete molecular response and may be a path to a CML cure.
Abstract: All available data from ongoing studies of second-generation tyrosine kinase inhibitors (TKIs) for treatment of patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) were reviewed. In two nilotinib phase 2 trials, the speed and depth of molecular and cytogenetic responses were greater than responses to imatinib. Furthermore, only one patient in each study progressed to accelerated or blastic phase. In the phase 3 ENESTnd study, molecular and cytogenetic responses to nilotinib were superior to imatinib, and more patients achieved undetectable levels of disease with nilotinib. Nilotinib also demonstrated significantly lower progression than did imatinib. In the ongoing phase 2 study of dasatinib, the speed and depth of molecular and cytogenetic responses were higher compared with expected responses to imatinib; no patient to date has progressed. In the phase 3 DASISION study, molecular and cytogenetic responses to dasatinib were superior to those of imatinib and fewer patients progressed. The results suggest that second-generation TKIs have the potential to replace imatinib as the standard of care for patients with early CML-CP. Future CML therapy might include earlier use of these agents to help more patients achieve complete molecular response and may be a path to a CML cure.
57 citations
TL;DR: Nilotinib is effective and well-tolerated for long-term use in patients with imatinib intolerance and leads to alleviation of AE-related symptoms and significant and durable responses.
55 citations
TL;DR: In this paper, the authors proposed a second-line treatment for chronic myeloid leukemia (CML) using the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) fusion oncoprotein.
Abstract: Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative neoplasm. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph), which results in the synthesis of the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) fusion oncoprotein, a constitutively active tyrosine kinase. The introduction of imatinib, a tyrosine kinase inhibitor (TKI) that is specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). For patients with CML, failure on standard-dose imatinib therapy (400 mg daily), imatinib dose escalation (600-800 mg daily) is a second-line option. However, high-dose imatinib is not an appropriate approach for patients who experience drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutation status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historic response, adverse-event tolerance, and risk factors.
TL;DR: The combination of lenalidomide plus prednisone appears to be more effective and safer than single-agent thalidomides or lenalidomside.
TL;DR: In this article, the authors analyzed the outcome of 435 patients with early chronic-phase, Philadelphia chromosome-positive CML treated with imatinib (n = 281), nilotinib(n = 78), and dasatinib-n = 76 using definitions of PFS and EFS used in the International Randomized Study of Interferon Versus STI571 (IRIS), Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENEST-nd), Dasatinib Versus Imatinib Study in Treatment-Na
Abstract: Purpose Different definitions of progression-free survival (PFS) and event-free survival (EFS) may result in perceived differences in outcomes with tyrosine kinase inhibitor (TKI) therapies in chronic myelogenous leukemia (CML). Patients and Methods We analyzed the outcome of 435 patients with early chronic-phase, Philadelphia chromosome–positive CML treated with imatinib (n = 281), nilotinib (n = 78), and dasatinib (n = 76) using definitions of PFS and EFS used in the International Randomized Study of Interferon Versus STI571 (IRIS), Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENEST-nd), Dasatinib Versus Imatinib Study in Treatment-Naive CML Patients (DASISION), and MD Anderson Cancer Center (MDACC) trials. Definitions for EFS-IRIS, time without progression in ENEST-nd, PFS-DASISION, and EFS-MDACC were as previously reported. The EFS-MDACC considered an event any instance of toxicity or death from any cause on or off therapy (if not counted before death as progre...
TL;DR: Patients with myelodysplastic syndromes whose disease has failed to respond to hypomethylating agent therapy should be referred for clinical trials when available.
TL;DR: This article guides the treating physician with a rational approach in the management of patients with chronic myeloid leukemia who fail initial treatment with imatinib or lose response while on therapy withImatinib.
Abstract: Imatinib mesylate has revolutionized the treatment landscape for patients with newly diagnosed chronic myeloid leukemia. Follow-up has shown excellent response rates, progression-free survival, and overall survival after 8 years. However, some patients develop resistance to imatinib treatment because of a multitude of reasons. Strategies to overcome resistance include dose escalation of imatinib or switching to a second-generation tyrosine kinase inhibitor or to one of the newer non-tyrosine kinase inhibitors. This article guides the treating physician with a rational approach in the management of patients with chronic myeloid leukemia who fail initial treatment with imatinib or lose response while on therapy with imatinib.
TL;DR: The authors conducted a phase 1/2 study of tipifarnib in combination with idarubicin and cytarabine in 95 patients with previously untreated acute myeloid leukemia (AML) or high‐risk myelodysplastic syndrome.
Abstract: BACKGROUND:
The authors conducted a phase 1/2 study of tipifarnib in combination with idarubicin and cytarabine (IA) in 95 patients with previously untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome.
METHODS:
Induction consisted of idarubicin 12 mg/m2 a day on days 1-3, cytarabine 1.5 g/m2 intravenously continuously daily on days 1-4 (days 1-3 if age ≥60 years), and tipifarnib, with the first cohort (n = 6) receiving 200 mg orally twice a day and all others receiving 300 mg twice a day for 21 days every 28 days. Consolidation consisted of 5 courses of idarubicin 8 mg/m2 a day on days 1-2, cytarabine 0.75 g/m2 a day on days 1-3, and tipifarnib 300 mg twice a day for 14 days every 4-6 weeks. Maintenance with tipifarnib 300 mg twice a day for 21 days every 4-6 weeks was continued for 6 months.
RESULTS:
With a median follow-up of 33 months, 61 patients achieved complete remission (CR) (64%), and 9 achieved complete remission with incomplete platelet recovery (CRp) (9%). The median duration of CR was not reached. Median overall survival was 17 months. The most common grade 3 adverse events were gastrointestinal toxicities, liver dysfunction, and skin rash. Compared with historical IA, IA and tipifarnib showed a better CR duration (P = .04) and a trend toward a higher CR rate in patients with chromosome 5/7 abnormalities.
CONCLUSIONS:
The combination of IA and tipifarnib is safe and active. Further studies exploring different dosages and schedules are warranted, particularly in patients with poor-risk AML. Cancer 2011. © 2010 American Cancer Society.
TL;DR: Patients with leukemia who develop ICH do not have universally poor outcomes, and a simple scoring system could serve to advise physicians and families of the prognosis and the potential benefit of aggressive treatment options.
Abstract: Intracranial hemorrhage (ICH) is associated with great morbidity and mortality in patients with acute leukemia. We identified 118 patients with ICH from a total of 2,421 patient with leukemia who were treated at our institution between 2005-2009, and assessed the prognostic factors for mortality in the ICH cohort. Median age at time of ICH was 58 years, 49% were male, and 60% had acute myeloid leukemia. The relative incidence of ICH was highest in patients with chronic myeloid leukemia in blast crisis (12.1%). Mental status changes were the most common symptom which prompted work-up for ICH. Median survival for all patients after onset of ICH was 20 days. In multivariate analyses, four clinical characteristics were identified as independent adverse factors for mortality in patients with ICH: albumin 835 U/L, age > 60 years, and relapsed disease status. Based on the number of risk factors, mortality after ICH was: 25% (0 risk factor), 47% (1), 78% (2), and >97% (3 or 4). In conclusion, patients with leukemia who develop ICH do not have universally poor outcomes, and a simple scoring system could serve to advise physicians and families of the prognosis and the potential benefit of aggressive treatment options.
TL;DR: Imatinib may overcome the adverse prognostic impact of deletions of derivative chromosome 9 in patients with chronic myeloid leukemia treated with hydroxyurea, interferon, or stem cell transplantation.
Abstract: BACKGROUND:
Deletions of derivative chromosome 9 are a poor prognostic factor in patients with chronic myeloid leukemia (CML) treated with hydroxyurea, interferon, or stem cell transplantation. Imatinib may overcome the adverse prognostic impact of deletions of derivative chromosome 9.
METHODS:
A study was undertaken to investigate the prognostic impact of deletions of derivative chromosome 9 in 353 patients with CML receiving the second generation tyrosine kinase inhibitors (TKIs) nilotinib (n = 161) or dasatinib (n = 192).
RESULTS:
Deletion of derivative chromosome 9 status was determined in 245 (69%). Twenty-eight (11%) patients, 22 in chronic phase, 4 in accelerated phase, and 2 in blast phase, carried deletions of derivative chromosome 9, including 17 receiving nilotinib and 11 receiving dasatinib (P = .47). Overall survival (OS) at 24 months was similar between patients with or without deletions of derivative chromosome 9 (70% vs 71%, P = .76). For patients in chronic phase, no significant differences in overall major cytogenetic response (77% vs 82%, P = .57) or complete cytogenetic response (77% vs 81%, P = .71) rates were observed between patients with or without deletions of derivative chromosome 9. At 24 months, patients with CML in chronic phase without deletions of derivative chromosome 9 had improved event-free survival (EFS) (88% vs 66%, P = .07) and OS (96% vs 82%; P = .08) compared with those carrying deletions of derivative chromosome 9. However, multivariate analysis established second-line versus frontline second generation TKI therapy as the only adverse prognostic factor for EFS and increased bone marrow blast burden and older age as independent adverse prognostic factors for OS.
CONCLUSIONS:
Deletions of derivative chromosome 9 do not appear to be an independent risk factor for survival among patients with CML in chronic phase receiving second generation TKIs. Cancer 2011;. © 2011 American Cancer Society.
TL;DR: The rationale for targeting aberrant DNA methylation in hematologic malignancies, in particular the myelodysplastic syndromes (MDS) and AML, and the pharmacokinetic data gained from low-dose decitabine are discussed.
Abstract: Introduction: Acute myeloid leukemia (AML) is a life-threatening malignancy that primarily afflicts an elderly population. Treatment of elderly patients with intensive chemotherapy is associated with high treatment-related morbidity and mortality. Therefore, less toxic approaches involving low-dose decitabine-based regimens are being explored in this patient population. Areas covered: This drug evaluation article discusses the rationale for targeting aberrant DNA methylation in hematologic malignancies, in particular the myelodysplastic syndromes (MDS) and AML. The authors review the pharmacokinetic data gained from low-dose decitabine, as well as the clinical progress of decitabine in the treatment of hematologic malignancies. Published manuscripts in English were selected from PubMed using a combination of the following search terms: acute myeloid leukemia, pharmacokinetics, decitabine, 5-aza-2′-deoxycytidine, DNA methylation, DNA methyltransferase, myelodysplastic syndrome and leukemia. Expert opinion:...
TL;DR: Prognosis in MDS is directly associated with the severity of thrombocytopenia, and it was predicted for worse outcome within each of the International Prognostic Scoring System risk groups.
Abstract: Purpose
To analyze the incidence and significance of thrombocytopenia in patients with myelodysplastic syndrome (MDS).
TL;DR: ARRY-614 is a small-molecule inhibitor of both p38 MAPK and Tie2 that may improve hematopoiesis in lower-risk MDS patients (pts) and evaluate safety, pharmacokinetics (PK), preliminary efficacy (IWG] 2006) and pharmacodynamic (PD) effects.
TL;DR: Although some patients may fail on therapy with imatinib, effective salvage therapy is available with second‐generation TKIs, and current measurement of efficacy for each therapy is judged by its individual impact on overall survival and event‐free survival (EFS).
Abstract: BACKGROUND:
Imatinib is an effective tyrosine kinase inhibitor (TKI) for patients with chronic myeloid leukemia (CML) in chronic phase (CP). Although some patients may fail on therapy with imatinib, effective salvage therapy is available with second-generation TKIs. Current measurement of efficacy for each therapy is judged by its individual impact on overall survival and event-free survival (EFS).
METHODS:
In total, 586 patients with CML in CP who received imatinib were included in this analysis in 2 cohorts: imatinib as front-line therapy (n = 281) or after failure on interferon-α (IFN-α) (n = 305). By accounting for successful salvage treatment (ie, regain of complete cytogenetic response), the current EFS (CEFS) rate was calculated to obtain a more accurate impression of the outcome of patients with CML who received treatment with sequential TKIs.
RESULTS:
For patients who received imatinib after failing on IFN-α, the 7-year EFS rate was 61%, whereas the CEFS rate was 69%. The 7-year EFS rate for patients who received imatinib as initial therapy was 81% compared with a 7-year CEFS rate of 88%.
CONCLUSIONS:
CEFS provided a more accurate representation of the outcome of patients with CML in CP. These patients may frequently be treated successfully with subsequent TKIs after experiencing failure on the first TKI. Cancer 2011. © 2010 American Cancer Society
TL;DR: The efficacy and safety of nilotinib as frontline therapy for pts with newly diagnosed CML-CP and the proportion of pts attaining major molecular response (MMR) at 12 months (mo) are investigated.
TL;DR: The management of chronic myeloid leukemia (CML) has been revolutionized by the availability of small molecule tyrosine kinase inhibitors (TKI), such as imatinib (formerly STI571), dasatinib, and nilotinib.
Abstract: The management of chronic myeloid leukemia (CML) has been revolutionized by the availability of small molecule tyrosine kinase inhibitors (TKI), such as imatinib (formerly STI571), dasatinib, and nilotinib. These agents work by competing with adenosine triphosphate (ATP) at its binding site on the
TL;DR: Patients with more than one BCR-ABL1 mutation fare worse than those with no or one mutation in chronic myeloid leukemia post-imatinib failure, and overall survival rates are worse.
Abstract: We investigated the impact of carrying more than one BCR-ABL1 mutation in 207 patients with chronic myeloid leukemia (102 chronic, 61 accelerated, and 44 blast phase) post-imatinib failure. Seven (8%) of 92 patients carrying mutations had more than one mutation: 4 (4%) in chronic phase, 2 (2%) in accelerated phase, and one (1 %) in blast phase. The cytogenetic response rate to second generation TKIs for patients with no, one, or more than one mutation was 88%, 69%, 50% (P=0.03) in chronic phase, 54%, 42%, 50% in accelerated phase (P=0.67), and 35%, 25%, 0% (P=0.63) in blast phase, respectively. No differences were observed in event free survival or overall survival in accelerated or blast phase according to their mutational status. However, the 4-year event free survival rates among patients in chronic phase with no, one, or more than one BCR-ABL1 mutation were 56%, 49%, and 0%, respectively (P=0.02), with overall survival rates of 91%, 69%, and 75%, respectively (P=0.13). In conclusion, patients with more than one BCR-ABL1 mutation fare worse than those with no or one mutation.
TL;DR: In Philadelphia-positive (Ph-positive) acute lymphoblastic leukemia (ALL), the addition of imatinib improved response rates, however, short remission durations with single agent therapy limit the benefit on survival.
Abstract: Although imatinib revolutionized the management of chronic myeloid leukemia (CML), recent data indicate a transformation in the treatment approach likely in the near future. The superiority of second-generation tyrosine kinase inhibitors (TKIs) over imatinib in newly diagnosed disease has been recognized. Several investigational agents specific for those patients with the T315I mutation remain under evaluation. In Philadelphia-positive (Ph-positive) acute lymphoblastic leukemia (ALL), the addition of imatinib improved response rates. However, short remission durations with single agent therapy limit the benefit on survival. Early molecular remissions achieved with dasatinib will enable more patients to proceed to stem cell transplant (SCT), with increased likelihood of positive outcomes post-SCT.
TL;DR: CCyR is associated with the greatest survival benefit among patients treated with second-line therapy or beyond and remains the optimal cytogenetic goal of therapy.
Abstract: Many patients with chronic myeloid leukemia who have failed initial therapy with a tyrosine kinase inhibitor achieve a cytogenetic response that is not complete (ie, partial or minor). This study analyzes the clinical benefit of such responses and identifies value in achieving such responses. Patients with less than complete cytogenetic response to second -line therapy or beyond should be considered to have benefit from therapy and the value of this considered in the context of which alternative options are available. Background Complete cytogenetic response (CCyR) is the gold standard for response to therapy for patients with chronic myeloid leukemia (CML) because it is associated with a survival benefit. However, patients who have failed initial therapy with a tyrosine kinase inhibitor (TKI) frequently achieve only partial or minor cytogenetic responses. The clinical benefit of such responses is unclear. Patients and Methods We analyzed the records of all 165 consecutive patients treated in clinical trials with TKI as second-line therapy or beyond after failure to prior imatinib therapy. Results A CCyR was achieved with second-line TKI therapy or beyond in 52% of patients, whereas 7% achieved a partial cytogenetic response (PCyR), 14% a minor cytogenetic response (mCyR), 14% complete hematologic response (CHR) only, and 17% no response. The 3-year survival probability was 98% for those with CCyR, compared to 83% with PCyR, 83% for mCyR, 76% for CHR, and 71% for no response. Survival free from transformation rates at 3 years were 93%, 73%, 84%, 88%, and 0%, respectively. Conclusions CCyR is associated with the greatest survival benefit among patients treated with second-line therapy or beyond and remains the optimal cytogenetic goal of therapy. However, patients with partial and minor cytogenetic response derive a benefit compared to patients who have no response. This benefit should be recognized and evaluated against any alternative option available to a given patient before a change in therapy is recommended.
TL;DR: The case of a 57-year-old man diagnosed with CML in 2003 in whom imatinib therapy failed after which he acquired the T315I mutation is reported, illustrating the benefit of combination therapy that includes a TKI and a second agent with a different mechanism of action, in eradicating resistant disease with the T 315I clone.
Abstract: Mutations of BCR-ABL1 are observed in 50% of patients with imatinib-resistant chronic myeloid leukemia (CML) The T315I mutation is resistant to imatinib and second-generation tyrosine kinase inhibitors (TKIs) We report the case of a 57-year-old man diagnosed with CML in 2003 in whom imatinib therapy failed after which he acquired the T315I mutation He was treated sequentially with an anti-T315I–specific agent, KW-2449, that led to eradication of the mutation without any further improvement Subsequent introduction of combination therapy that included dasatinib and pegylated interferon led to the achievement of a sustained complete cytogenetic and major molecular response (MMR) This case illustrates the benefit of combination therapy that includes a TKI and a second agent with a different mechanism of action, either sequentially (TKI followed by KW-2449) or concomitantly (TKI + interferon), in eradicating resistant disease with the T315I clone