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ABSTRACT: BACKGROUND: We assessed for CD30 expression in patients with acute myeloid leukemia (AML) or high-grade myelodysplastic syndrome (MDS) to examine the possibility that anti-CD30 could be targeted therapy in these patients. METHODS: Multicolor flow cytometry immunophenotypic analysis was performed on bone marrow aspirates of 135 patients with AML or MDS and peripheral blood samples in a subset of 33 patients. Immunohistochemistry was performed on bone marrow aspirate clot specimens of 84 patients. RESULTS: The median patient age was 63 years (range, 13-92 years); 102 (75%) patients had refractory or recurrent disease, and 68 (50%) had high-risk cytogenetics. Overall, the median percentage of blasts positive for CD30 was 14% (range, 0%-91%). By using an arbitrary 20% cutoff, 49 (36%) patients were considered to have CD30 expression. Monocytic cells, either mature or immature, were consistently negative for CD30. Therefore, CD30 expression was less in AML with monocytic differentiation (P = .006). The patients with persistent disease who had been actively treated had a higher level of CD30 expression than the patients who were untreated (P = .031). In paired samples, CD30 expression was consistently higher in bone marrow blasts than in peripheral blood blasts (P = .002). Immunohistochemistry demonstrated CD30 expression by myeloblasts in a subset of patients, but reactivity was generally weaker and focally compared. CONCLUSIONS: CD30 is expressed by myeloblasts in a substantial subset of patients with AML or MDS. Because the study group was composed mostly of patients with high-risk AML or MDS in whom very few treatment options are available, these data raise the possibility that anti-CD30-targeted therapy could be a potential option for this patient group.
Clinical lymphoma, myeloma & leukemia 01/2013;
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ABSTRACT: BACKGROUND: Myelodysplastic syndromes (MDS) progress to acute myeloid leukemia (AML) in approximately 30% of patients. Identification of risk factors for progression to AML and overall survival (OS) would help guide treatment decisions. PATIENTS AND METHODS: We investigated prognostic factors for progression to AML and survival in 163 patients with MDS treated with decitabine 15 mg/m(2) over 3 hours every 8 hours for 3 days every 6 weeks (n = 74) or 20 mg/m(2) over 1 hour daily for 5 days every 4 weeks (n = 89). RESULTS: Multivariate analysis of pooled baseline data revealed that only study effect was associated with progression to AML. A hemoglobin value at least 10 g/dL, platelet count at least 50 × 10(3)/μL, and lack of chromosome 5 or 7 abnormalities were associated with longer OS. CONCLUSIONS: Patients with certain prognostic factors should be considered for other interventions in addition to decitabine treatment.
Clinical lymphoma, myeloma & leukemia 12/2012;
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Jorge E Cortes,
Hagop Kantarjian,
Neil P Shah,
Dale Bixby,
Michael J Mauro,
Ian Flinn,
Thomas O'Hare,
Simin Hu,
Narayana I Narasimhan,
Victor M Rivera,
Tim Clackson,
Christopher D Turner,
Frank G Haluska,
Brian J Druker,
Michael W N Deininger,
Moshe Talpaz
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ABSTRACT: Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors.
In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140).
Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response.
Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.).
New England Journal of Medicine 11/2012; 367(22):2075-88. · 53.30 Impact Factor
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ABSTRACT: BACKGROUND: A previous survey of physician self-reported practice patterns in the management of CML was conducted in 2005. The National Comprehensive Cancer Network and European LeukemiaNet guidelines now include nilotinib and dasatinib in their treatment algorithms for CML. To assess these new guidelines, a cross-sectional survey of US hematologists and/or oncologists was conducted in December 2010 through an online survey. MATERIALS AND METHODS: The survey had 43 questions consisting of items updated from the 2005 survey to reflect changes in clinical practice, tyrosine kinase inhibitor therapy, and current guidelines. RESULTS: Analysis of the responses from 507 board certified medical oncologists/hematologists suggests that the use of imatinib 400 mg as an initial treatment option had decreased from 62% in 2005 to 52% in the 2010 survey. Currently, nearly 40% of physicians would choose either nilotinib or dasatinib as first-line treatment. From the surveyed physicians, achievement of at least a major molecular response (MMR) is the predominant treatment goal in chronic phase CML. CONCLUSION: This survey emphasizes the need for continued updates and education regarding optimal therapy, monitoring practices, and therapeutic end points in CML.
Clinical lymphoma, myeloma & leukemia 10/2012;
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Jorge E Cortes,
Dong-Wook Kim,
Hagop M Kantarjian,
Tim H Brümmendorf,
Irina Dyagil,
Laimonas Griskevicius,
Hemant Malhotra,
Christine Powell,
Karïn Gogat,
Athena M Countouriotis,
Carlo Gambacorti-Passerini
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ABSTRACT: PURPOSE Bosutinib is an oral Src/Abl tyrosine kinase inhibitor. The phase III Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia (BELA) trial compared bosutinib with imatinib in newly diagnosed, chronic-phase chronic myeloid leukemia (CML). PATIENTS AND METHODS A total of 502 patients were randomly assigned 1:1 to bosutinib 500 mg per day or imatinib 400 mg per day. Results The complete cytogenetic response (CCyR) rate at 12 months was not different for bosutinib (70%; 95% CI, 64% to 76%) versus imatinib (68%; 95% CI, 62% to 74%; two-sided P = .601); therefore, the study did not achieve its primary end point. The major molecular response (MMR) rate at 12 months was higher with bosutinib (41%; 95% CI, 35% to 47%) compared with imatinib (27%; 95% CI, 22% to 33%; two-sided P < .001). Time to CCyR and MMR was faster with bosutinib compared with imatinib (two-sided P < .001 for both). On-treatment transformation to accelerated/blast phase occurred in four patients (2%) on bosutinib compared with 10 patients (4%) on imatinib. A total of three CML-related deaths occurred on the bosutinib arm compared with eight on the imatinib arm. The safety profiles of bosutinib and imatinib were distinct; GI and liver-related events were more frequent with bosutinib, whereas neutropenia, musculoskeletal disorders, and edema were more frequent with imatinib. CONCLUSION This ongoing trial did not meet its primary end point of CCyR at 12 months, despite the observed higher MMR rate at 12 months, faster times to CCyR and MMR, fewer on-treatment transformations to accelerated/blast phase, and fewer CML-related deaths with bosutinib compared with imatinib. Each drug had a distinct safety profile.
Journal of Clinical Oncology 09/2012; 30(28):3486-92. · 18.37 Impact Factor
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ABSTRACT: Skeletal integrity is sustained by osteoblast-osteoclast interactions, controlled by several signaling pathways that include tyrosine kinases. Imatinib is a tyrosine kinase inhibitor with an extended therapeutic range based on its ability to differentially bind to receptor and nonreceptor tyrosine kinases. In this study, we used digital image analysis to assess changes in trabecular bone surface area within bone marrow biopsy specimens of 34 patients with chronic phase chronic myelogenous leukemia treated with single-agent imatinib. These patients were 25 men and 9 women with a median age of 59 years. We selected representative areas of paired bone marrow biopsy specimens obtained at baseline and within the subsequent 48 months. Computer-assisted analysis was performed to calculate trabecular bone area (TBA) within the sample by using the equation TBA% = sum of trabecular area/total biopsy specimen area. Percentage changes were defined as ΔTBA% and were arbitrarily subdivided into marked (>50%), moderate (10%-50%), and mild (<10%). During the study interval, TBA% increased in 24 patients (71%) and decreased in 10 patients (29%). Overall, there was a significant increase in TBA% (P = .02). No correlation was found between changes in trabecular bone area and either clinical or cytogenetic response (P = .25). The results show that imatinib therapy can alter trabecular bone in bone marrow biopsy specimens of chronic myelogenous leukemia patients, most often resulting in an increase in TBA%.
Human pathology 08/2012; · 3.03 Impact Factor
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Srdan Verstovsek,
Hagop M Kantarjian,
Zeev Estrov, Jorge E Cortes,
Deborah A Thomas,
Tapan Kadia,
Sherry Pierce,
Elias Jabbour,
Gautham Borthakur,
Elisa Rumi,
Ester Pungolino,
Enrica Morra,
Domenica Caramazza,
Mario Cazzola,
Francesco Passamonti
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ABSTRACT: Ruxolitinib is JAK1/JAK2 inhibitor with established clinical benefit in myelofibrosis (MF). We analyzed long-term outcomes of 107 patients with intermediate-2 or high-risk MF receiving ruxolitinib at MD Anderson Cancer Center (MDACC) on phase 1/2 trial. After a median of 32 months of follow-up, 58 patients (54%) were still receiving ruxolitinib, with overall survival (OS) of 69%. The splenomegaly and symptom reductions achieved with ruxolitinib were sustained with long-term therapy. Therapy was well tolerated; discontinuation rates at 1, 2, and 3 years were 24%, 36%, and 46%, respectively. OS of 107 MDACC patients was significantly better (P = .005) than that of 310 matched (based on trial enrollment criteria) historical control patients, primarily because of highly significant difference in OS in the high-risk subgroup (P = .006). Furthermore, among MDACC patients, those with high-risk MF experienced the same OS as those with intermediate-2 risk. Patients with ≥ 50% reduction in splenomegaly had significantly prolonged survival versus those with < 25% reduction (P < .0001). Comparison of discontinuation rates and reasons for stopping the therapy to those reported for other 51 patients in the phase 1/2 trial, and 155 ruxolitinib-treated patients in phase 3 COMFORT-I study, suggest that continued therapy with ruxolitinib at optimal doses contributes to the benefits seen, including OS benefit.
Blood 06/2012; 120(6):1202-9. · 9.90 Impact Factor
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ABSTRACT: FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia and is associated with worse clinical outcome. Changes in FLT3 mutation status can occur during the course of disease, but the clinical impact of a change is unclear. We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution between May 2002 and January 2011. We found that 42 (6.2%) out of 680 patients with FLT3 mutation experienced a change of FLT3 mutation status. In all, 36 patients with wild-type FLT3 at the time of initial diagnosis gained mutation (Negative/Positive) and six initially FLT3-mutated patients became wild type during their following relapses (Positive/Negative). The 5-year survival of these patients was similar to that of patients with persistently wild-type FLT3 (Negative/Negative; P=0.464), and significantly better than patients who had stable FLT3 mutation during their disease course (Positive/Positive; P<0.001). However, after mutations became detectable in the Negative/Positive group, the forward survival of these patients tracked that of the Positive/Positive group after relapse (P=0.761). In addition, we did not find a significant difference in survival between patients with internal tandem duplications and those with point mutations in the tyrosine kinase domain of the FLT3 gene. These results suggest that FLT3 mutations are unstable and that there is potential clinical value in continuously monitoring FLT3 mutation status.
Modern Pathology 06/2012; 25(10):1405-12. · 4.79 Impact Factor
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Rajesh R Singh,
Ashish Bains,
Keyur P Patel,
Hamed Rahimi,
Bedia A Barkoh,
Abhaya Paladugu,
Tigist Bisrat,
Farhad Ravandi-Kashani, Jorge E Cortes,
Hagop M Kantarjian,
L Jeffrey Medeiros,
Rajyalakshmi Luthra
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ABSTRACT: DNA methyltransferase 3A (DNMT3A) is mutated in a subset of de novo acute myeloid leukemia patients and is associated with poor overall and event-free survival. Because routine Sanger sequencing of the 23 DNMT3A exons is impractical in clinical laboratories, we developed a high-throughput method using high-resolution melting (HRM) analysis, which identifies sequence variants by detecting subtle changes in the melting patterns of mutant DNA in comparison with WT sequences. DNA from 104 acute myeloid leukemia patients was tested for mutations in 12 exons encoding 3 major functional domains of DNMT3A: the PWWP (proline-tryptophan-tryptophan-proline) domain (exons 8 to 10), the ADD (ATM-DNMT3-DNMT3L) zinc finger, and the methyltransferase domains encoded by exons 15 to 23. HRM analysis identified 20 of 104 patient samples as variants, which we confirmed by Sanger sequencing. Codon 882 of exon 23 was mutated at the highest frequency with an occurrence rate of 11.5%. All HRM WT calls were confirmed to be devoid of mutations by Sanger sequencing. We also identified seven novel and previously unreported DNMT3A mutations. Structural modeling showed seven of the eight missense mutations detected in our study increased the free energy, destabilized protein, and altered solvent accessibility, suggesting their loss-of-function nature. These data demonstrate HRM analysis to be a higher throughput, sensitive, and efficient alternative to Sanger sequencing for detecting DNMT3A mutations in the clinical diagnostic laboratory.
The Journal of molecular diagnostics: JMD 05/2012; 14(4):336-45. · 3.48 Impact Factor
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ABSTRACT: BACKGROUND: The impact of single versus multiple fms-like tyrosine kinase receptor 3 internal tandem duplication (FLT3-ITD) mutations on the clinical outcome of patients with acute myelogenous leukemia has not been well studied, and particularly has not been investigated while simultaneously accounting for the quantitative mutation burden. METHODS: The authors conducted a multivariate analysis of overall survival, event-free survival, and complete remission duration, including numeric variation (single vs multiple) and quantitative mutant burden of FLT3-ITD as variables among other clinically relevant factors. RESULTS: An analysis of a cohort of 1043 patients with AML demonstrated that, among patients with normal-karyotype acute myelogenous leukemia and FLT3-ITD mutation, overall survival and event-free survival were not affected by the number of FLT3-ITD mutations, but complete remission duration was significantly longer in patients who had multiple FLT3-ITD mutations (median, 86 weeks vs 34 weeks; P = .03). CONCLUSIONS: The current results indicated that time-to-event analyses of patients with normal-karyotype acute myelogenous leukemia and FLT3-ITD mutation should take into account the number of mutations and the mutant burden, among other factors. Cancer 2012. © 2012 American Cancer Society.
Cancer 05/2012; · 4.77 Impact Factor
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Guillermo Garcia-Manero,
Francesco Paolo Tambaro,
Nebiyou B Bekele,
Hui Yang,
Farhad Ravandi,
Elias Jabbour,
Gautam Borthakur,
Tapan M Kadia,
Marina Y Konopleva,
Stefan Faderl, Jorge E Cortes,
Mark Brandt,
Yumin Hu,
Deborah McCue,
Willie Mae Newsome,
Sherry R Pierce,
Marcos de Lima,
Hagop M Kantarjian
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ABSTRACT: To evaluate the safety and efficacy of the combination of the histone deacetylase inhibitor vorinostat with idarubicin and ara-C (cytarabine) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS).
Patients with previously untreated AML or higher-risk MDS age 15 to 65 years with appropriate organ function and no core-binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m(2) intravenously (IV) daily × 3 (days 4 to 6), and cytarabine 1.5 g/m(2) IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy and up to 12 months of maintenance therapy with single-agent vorinostat. The study was designed to stop early if either excess toxicity or low probability of median event-free survival (EFS) of more than 28 weeks was likely.
After a three-patient run-in phase, 75 patients were treated. Median age was 52 years (range, 19 to 65 years), 29 patients (39%) were cytogenetically normal, and 11 (15%) had FLT-3 internal tandem duplication (ITD). No excess vorinostat-related toxicity was observed. Induction mortality was 4%. EFS was 47 weeks (range, 3 to 134 weeks), and overall survival was 82 weeks (range, 3 to 134 weeks). Overall response rate (ORR) was 85%, including 76% complete response (CR) and 9% in CR with incomplete platelet recovery. ORR was 93% in diploid patients and 100% in FLT-3 ITD patients. Levels of NRF2 and CYBB were associated with longer survival.
The combination of vorinostat with idarubicin and cytarabine is safe and active in AML.
Journal of Clinical Oncology 05/2012; 30(18):2204-10. · 18.37 Impact Factor
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H Jean Khoury, Jorge E Cortes,
Hagop M Kantarjian,
Carlo Gambacorti-Passerini,
Michele Baccarani,
Dong-Wook Kim,
Andrey Zaritskey,
Athena Countouriotis,
Nadine Besson,
Eric Leip,
Virginia Kelly,
Tim H Brümmendorf
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ABSTRACT: Bosutinib, a dual Src/Abl tyrosine kinase inhibitor (TKI), has shown potent activity against chronic myeloid leukemia (CML). This phase 1/2 study evaluated the efficacy and safety of once-daily bosutinib 500 mg in leukemia patients after resistance/intolerance to imatinib. The current analysis included 118 patients with chronic-phase CML who had been pretreated with imatinib followed by dasatinib and/or nilotinib, with a median follow-up of 28.5 months. In this subpopulation, major cytogenetic response was attained by 32% of patients; complete cytogenetic response was attained by 24%, including in one of 3 patients treated with 3 prior TKIs. Complete hematologic response was achieved/maintained in 73% of patients. On-treatment transformation to accelerated/blast phase occurred in 5 patients. At 2 years, Kaplan-Meier-estimated progression-free survival was 73% and estimated overall survival was 83%. Responses were seen across Bcr-Abl mutations, including those associated with dasatinib and nilotinib resistance, except T315I. Bosutinib had an acceptable safety profile; treatment-emergent adverse events were primarily manageable grade 1/2 gastrointestinal events and rash. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (8%) and rash (4%). Bosutinib may offer a new treatment option for patients with chronic-phase CML after treatment with multiple TKIs. This trial was registered at www.clinicaltrials.gov as NCT00261846.
Blood 02/2012; 119(15):3403-12. · 9.90 Impact Factor
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Hagop M Kantarjian,
Neil P Shah, Jorge E Cortes,
Michele Baccarani,
Mohan B Agarwal,
María Soledad Undurraga,
Jianxiang Wang,
Juan Julio Kassack Ipiña,
Dong-Wook Kim,
Michinori Ogura,
Carolina Pavlovsky,
Christian Junghanss,
Jorge H Milone,
Franck E Nicolini,
Tadeusz Robak,
Jan Van Droogenbroeck,
Edo Vellenga,
M Brigid Bradley-Garelik,
Chao Zhu,
Andreas Hochhaus
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ABSTRACT: Dasatinib is a highly potent BCR-ABL inhibitor with established efficacy and safety in imatinib-resistant/-intolerant patients with chronic myeloid leukemia (CML). In the phase 3 DASISION trial, patients with newly diagnosed chronic-phase (CP) CML were randomized to receive dasatinib 100 mg (n = 259) or imatinib 400 mg (n = 260) once daily. Primary data showed superior efficacy for dasatinib compared with imatinib after 12 months, including significantly higher rates of complete cytogenetic response (CCyR), confirmed CCyR (primary end point), and major molecular response (MMR). Here, 24-month data are presented. Cumulative response rates by 24 months in dasatinib and imatinib arms were: CCyR in 86% versus 82%, MMR in 64% versus 46%, and BCR-ABL reduction to ≤ 0.0032% (4.5-log reduction) in 17% versus 8%. Transformation to accelerated-/ blast-phase CML on study occurred in 2.3% with dasatinib versus 5.0% with imatinib. BCR-ABL mutations, assessed after discontinuation, were detected in 10 patients in each arm. In safety analyses, fluid retention, superficial edema, myalgia, vomiting, and rash were less frequent with dasatinib compared with imatinib, whereas pleural effusion and grade 3/4 thrombocytopenia were more frequent with dasatinib. Overall, dasatinib continues to show faster and deeper responses compared with imatinib, supporting first-line use of dasatinib in patients with newly diagnosed CML-CP. This study was registered at ClinicalTrials.gov: NCT00481247.
Blood 12/2011; 119(5):1123-9. · 9.90 Impact Factor
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ABSTRACT: Outcome in acute myeloid leukemia (AML) worsens with age, at least in part because of higher treatment-related mortality (TRM) in older patients. Eligibility for intensive AML treatment protocols is therefore typically based on age as the implied principal predictor of TRM, although other health- and disease-related factors modulate this age effect.
We empirically defined TRM using estimated weekly hazard rates in 3,365 adults of all ages administered intensive chemotherapy for newly diagnosed AML. We used the area under the receiver operator characteristic curve (AUC) to quantify the relative effects of age and other covariates on TRM in a subset of 2,238 patients. In this approach, an AUC of 1.0 denotes perfect prediction, whereas an AUC of 0.5 is analogous to a coin flip.
Regardless of age, risk of death declined once 4 weeks had elapsed from treatment start, suggesting that patients who die during this time comprise a qualitatively distinct group. Performance status (PS) and age were the most important individual predictors of TRM (AUCs of 0.75 and 0.65, respectively). However, multicomponent models were significantly more accurate in predicting TRM (AUC of 0.83) than PS or age alone. Elimination of age from such multicomponent models only minimally affected their predictive accuracy (AUC of 0.82).
These data suggest that age is primarily a surrogate for other covariates, which themselves add significantly to predictive accuracy, thus challenging the wisdom of using age as primary or sole basis for assignment of intensive, curative intent treatment in AML.
Journal of Clinical Oncology 11/2011; 29(33):4417-23. · 18.37 Impact Factor
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ABSTRACT: 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).
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.
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 of suboptimal response were 0%, 2%, 1%, and 12% at 3, 6, 12, and 18 months of therapy, respectively. There was no difference in EFS and CCyR duration between patients who achieved CCyR with and without MMR across all the landmark times of 3, 6, 12, and 18 months.
The use of second-generation TKIs as initial therapy in CML induces high rates of CCyR at early time points. The ELN definitions of response proposed for imatinib therapy are not applicable in this setting. We propose that achievement of CCyR and partial cytogenetic response at 3 months should be considered optimal and suboptimal responses, respectively. 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.
Journal of Clinical Oncology 11/2011; 29(32):4260-5. · 18.37 Impact Factor
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Jorge E Cortes,
Hagop M Kantarjian,
Tim H Brümmendorf,
Dong-Wook Kim,
Anna G Turkina,
Zhi-Xiang Shen,
Ricardo Pasquini,
H Jean Khoury,
Steven Arkin,
Angela Volkert,
Nadine Besson,
Richat Abbas,
Junyuan Wang,
Eric Leip,
Carlo Gambacorti-Passerini
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ABSTRACT: Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinib-intolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846.
Blood 08/2011; 118(17):4567-76. · 9.90 Impact Factor
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ABSTRACT: Anemia is an expected consequence of intensive chemotherapy regimens administered to patients with acute leukemia. This study was designed to determine whether epoetin alpha would decrease the number of transfusion events and units of packed erythrocytes (PRBCs) transfused, and the secondary objective was to study the effects of epoetin alpha on quality of life (QOL) and complete remission (CR) rates.
Patients with acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LL), or Burkitt lymphoma (BL) who were receiving frontline myelosuppressive chemotherapy were randomized to receive epoetin alpha or no epoetin during the first 6 cycles of their planned chemotherapy. QOL was assessed by using the Edmonton Symptom Assessment Scale (ESAS) and the Functional Assessment of Cancer Therapy (FACT)-Anemia questionnaires.
Fifty-five patients were randomized to receive epoetin alpha, and 54 patients received no epoetin. Transfusion data were available for 79 of 81 evaluable patients (98%) who completed the treatment/observation period. The trial was stopped early because of poor accrual before the target of 123 evaluable patients was met. A mean of 10.6 units of PRBCs over 5 months were administered to those who received epoetin alpha compared with 13 units for those who did not receive epoetin (P = .04). There was no significant difference in QOL as assessed by the FACT-Anemia or ESAS instruments. The CR rate and the 3-year CR duration were not affected adversely by use of epoetin alpha.
Epoetin alpha decreased the number of PRBC transfusions and did not appear to have a negative impact on remission duration. No difference in QOL was observed.
Cancer 07/2011; 118(3):848-55. · 4.77 Impact Factor
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ABSTRACT: Pim kinases are Ser/Thr kinases with multiple substrates that affect survival pathways. These proteins are overexpressed in acute myeloid leukemia (AML) blasts and we hypothesized that Pim kinase inhibition would affect AML cell survival. Imidazo[1,2-b]pyridazine compound, SGI-1776 inhibits Pim-1, Pim-2 and Pim-3, and was evaluated in AML-cell line, -xenograft model, and -primary blasts. Treatment of AML cells with SGI-1776 results in a concentration-dependent induction of apoptosis and we investigated its effect on Pim kinase functions. Phosphorylation of traditional Pim kinase targets, c-Myc(Ser62) and 4E-BP1 (Thr36/Thr47), were both decreased in actively cycling AML cell lines MV-4-11, MOLM-13 and OCI-AML-3. Levels of antiapoptotic proteins Bcl-2, Bcl-x(L), XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed. This was correlated with inhibition of global RNA and protein synthesis and MCL-1 transcript decline after SGI-1776 treatment. These data suggest that SGI-1776 mechanism in AML involves Mcl-1 protein reduction. Consistent with cell line data, xenograft model studies with mice bearing MV-4-11 tumors showed efficacy with SGI-1776. Importantly, SGI-1776 was also cytotoxic in AML primary cells, irrespective of FLT3 mutation status and resulted in Mcl-1 protein decline. Pim kinase inhibition may be a new strategy for AML treatment.
Blood 05/2011; 118(3):693-702. · 9.90 Impact Factor
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ABSTRACT: The impact of FMS-like tyrosine kinase 3 (FLT3) mutations and mutation burden among cytogenetic subgroups of patients with acute myeloid leukemia (AML) other than normal karyotype (NK) AML is unclear.
Patients with newly diagnosed AML were divided among 3 cytogenetic subgroups: core binding factor (CBF) AML, NK-AML, and poor-risk AML.
In total, 481 patients were included: 13% had, CBF-AML, 57% had NK-AML, and 30% had poor risk AML, and the frequency of any FLT3 mutations was 20%, 32%, and 7.6% in the respective cytogenetic subgroups. FLT3 mutation did not have an impact on event-free survival (EFS) in patients with CBF-AML (P = .84) and poor-risk AML (P = .37). In patients with NK-AML, EFS was worse in the FLT3-internal tandem duplication (ITD) group (20 weeks vs 41 weeks; P < .00,001) but not in the FLT3-tyrosine kinase domain (TKD) point mutation group (61 weeks vs 41 weeks; P = .15). Worse EFS and overall survival (OS) were observed among patients with NK-AML and higher FLT3-ITD burden but not among patients with FLT3-TKD mutation. In multivariate analysis, FLT3-ITD mutation was prognostic of EFS in patients with NK-AML (hazard ratio, 3.1; P = .03).
FLT3 mutations did not have a prognostic impact in patients with AML who had good-risk and poor-risk karyotypes. In patients with NK-AML, FLT3-ITD mutations led to worse survival, which was even worse among patients who had high mutation burden.
Cancer 05/2011; 117(10):2145-55. · 4.77 Impact Factor
