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  • 1
    In: Clinical Leukemia, Elsevier BV, Vol. 1, No. 1 ( 2006-9), p. 57-60
    Type of Medium: Online Resource
    ISSN: 1931-6925
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2006
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  • 2
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4433-4433
    Abstract: Background: Aberrant over-expression of BCL-2 is a poor prognostic factor in patients with DLBCL. t(14;18) (q32;q21) results in transcription of the anti-apoptotic BCL-2 protein. In vitro studies have shown that rituximab induces an IL-10 dependent down regulation of BCL-2 and sensitizes cancer cells to the effect of chemotherapy agents. It has been reported that the addition of rituximab to chemotherapy has eliminated the prognostic significance of BCL-2 over-expression in DLBCL. However limited information is available regarding the prognostic significance of BCL-2 over-expression driven by t(14;18) following rituximab/chemoimmunotherapy. To this end we correlate the levels of Bcl-2 expression and response to front-line treatment in patients with primary refractory DLBCL (PR-DLBCL). Methods: A single-institution retrospective data analysis was done to identify all DLBCL patients treated between 1/1/02 and 12/31/06. Patients with PR-DLBCL, as defined by residual disease at the end of primary treatment or disease relapse within 6 months of completing it were identified. Patient demograpics, international prognostic index (IPI) score, treatments administered, outcome and Bcl-2 status were reviewed. Bcl-2 translocation was studied by a nested PCR-based assay of peripheral blood samples. The test is reproducibly sensitive to a detection level of 1:105 and reported the presence or absence of t(14;18) as a positive or negative result. BCL-2 protein expression in tissue was studied with immunohistochemistry (IHC). Results: A total of 246 patients with DLBCL were identified. Of these, 27 (11%) qualified as PR-DLBCL. Median age at diagnosis was 56 years (range 16–84). Thirteen (48%) were females and 14 (52%) were males. IPI score was 0 in 2 (7.5%), 1 in 9 (33.3%), 2 in 6 (22.2%), 3 in 4 (14.8%) and 4 in 6 (22.2%) patients. Disease was labeled ‘bulky’ ( 〉 5 cm lymphadenopathy) in 11 (41%) patients at the time of diagnosis. Twenty four (89%) patients received an initial rituximab-containing regimen and radiation therapy was administered to 13 (48%) patients. Median overall survival for all the 27 patients was 570 days (range 151–1437). Ten (37%) patients received peripheral blood stem cell transplantation during the course of their disease. At the time of analysis, 14 (52%) patients were alive and of these, 7 (50%) had persistent disease, while the other 7 (50%) were disease-free. t(14;18) data was available on 18 of these 27 patients and all were negative for the translocation. All of these 18 patients had received rituximab-containing initial therapy. Of these 18 patients, IHC for BCL-2 expression was available for 8 (44%), and was positive in all 8 patients. Conclusions: Bcl-2 over-expression is observed in a significant number of patients with primary rituximab/chemotherapy refractory DLBCL. In our selected group of patients, the t(14;18) does not appear to play a role in the expression of BCL-2, suggesting the existence of additional mechanisms responsible for BCL-2 upregulation. In addition, 70% of our PR-DLBCL patients did not express BCL-2, leading to the hypothesis that various regulatory proteins such as other members of the BH3 domain family play a role in determining rituximab/chemotherapy sensitivity.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 3
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4895-4895
    Abstract: Abstract 4895 Background Multiple myeloma (MM) remains an incurable cancer. Several biological and environmental factors have been considered to contribute to its pathogenesis, but so far no clear etiology is known. It remains undetermined if geographical differences and variability in environmental factors influences biological behavior and clinical presentation of MM patients. In depth research into the regional and demographic variation of these characteristics has not yet been done. To evaluate the impact of environmental influences we compared MM disease characteristics in two distinct geographical regions. Methods Patients with plasma cell disorders seen in the malignant hematology clinics of the University of Southern California (USC), Los Angeles, CA and the Multiple Myeloma Program Clinic at the Roswell Park Cancer Institute (RPCI), Buffalo, NY were included in this analysis. Demographic and disease-related clinical characteristics at the time of diagnosis of active MM were evaluated. Chi-square test or Mann-Whitney U test were used where appropriate. A 0.05 nominal significance level was used in all hypothesis testing. Results One hundred and sixty patients at USC and 170 patients at RPCI were studied. Among these, 140 and 144 had active MM at the time of diagnosis, respectively. The median age at diagnosis was 58 years (range 20-85) and 60 years (range 35-83), and males represented 48% and 52 % of the patients, respectively in the two geographic locations. Predominant patient race was Hispanic at USC (54%) and Caucasian at RPCI (92%). Advanced stage disease ( 〉 stage 1) was present in 87% and 85% patients, respectively as per the Durie Salmon (DS) staging and 53% and 48%, respectively as per the International Staging System (ISS). IgG MM was the most common subtype in both locations, but there were a higher number of patients on the West coast with LCO disease (22% vs. 10%). Lytic lesions were noted at the time of diagnosis in 59% of the patients at USC and 78% of the patients at RPCI while non-secretory MM was noted in 9% and 10% of the patients, respectively. There was a statistically significant difference between the patient populations in the two geographical regions with respect to median age at diagnosis (p=0.048), patient race (p 〈 0.001), disease subtype (p=0.018), and presence of lytic bone disease at diagnosis (p 〈 0.001). The difference in median age at diagnosis remained statistically significant even when patients were divided into age cohorts of 〈 50 yrs, 〈 60 yrs, 〈 70 yrs and ≥70 yrs (p=0.03). There was no statistically significant difference between the two groups of patients for gender (p=0.48), DS stage (p=0.22), renal dysfunction (p=0.77), ISS stage (p=0.62), light chain subtype (p=0.72), or secretor status (p=0.75). To ensure that these variations were not just due to ethnic differences, the Caucasian population at USC (n=30) was compared with the Caucasian population at RPCI (n=133). Disease subtype and presence of lytic bone lesions were still significantly different between these groups (p=0.04, and p=0.02, respectively). Conclusions Despite widespread heterogeneity amongst MM patients, variations in disease characteristics amongst geographically distinct regions have not been studied systematically. Our investigation represents the first attempt to compare patient characteristics from the West and East coasts of USA. We observe several demographic and clinical characteristics that were significantly different between the two populations that could not be explained based on ethnic influences of the study population. These differences in clinical characteristics may represent undefined environmental influences that are unique to geographic location of the patient(s) and can potentially influence disease biology. Our pilot observation will need validation in a larger patient population to better understand the influences mediated by environmental factors and geographic diversity on clinical and biological behavior of the disease. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 4
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4844-4844
    Abstract: Introduction: Bortezomib, a proteasome inhibitor is an effective antimyeloma therapy. We recently reported that multiple myeloma patients treated with bortezomib or bortezomib based regimen resulted in a higher incidence of herpes zoster (HZ). The exact etiology of this side effect remains unknown though our investigation demonstrated prolonged lymphopenia among patients treated with bortezomib. The high incidence of HZ among bortezomib treated patients prompted to prospectively investigate the role of antiviral prophylaxis in this patient population. Here we report for the first time the efficacy of acyclovir as prophylaxis for bortezomib associated HZ. Patients and Methods: We prospectively evaluated the impact of oral acyclovir (400mg PO twice daily for the duration of bortezomib therapy) on the incidence of HZ. All patients with multiple myeloma who were treated with bortezomib or bortezomib based regimens, and received prophylactic acyclovir were evaluable for this analysis. To compare the overall proportion of HZ among patients who received acyclovir prophylaxis and the historical control, Fisher exact test was used. Results: A total of 51 consecutive patients (27 M and 24 F) received acyclovir as prophylaxis. The median age was 61 (range 40–81 years), with advance stage MM noted in 86% (n=44) patients. Among these 69% had previously untreated MM while 31% had relapsed or refractory disease. Single agent bortezomib was given to 11 patients and 40 patients received bortezomib in combination with other antimyeloma agents (such as thalidomide, pegylated liposomal doxorubicin, dexamethasone, cyclophosphamide and/or lenalidomide). The overall incidence of HZ was 0% among patients receiving the acyclovir prophylaxis vs. 13% in the historical control. There was a significant difference in the overall proportion of HZ among patients who received acyclovir prophylaxis and the historical control (p = 0.0026). Conclusion: This is the first report on the efficacy of acyclovir for the prevention of bortezomib associated HZ in MM patients. While bortezomib is an effective antimyeloma therapy, an important side effect with significant morbidity is reactivation of HZ. Here we demonstrate for the first time that this side effect can be effectively prevented by oral acyclovir. Our observation warrants further evaluation. Considering significant morbidity associated with HZ we recommend the routine use of prophylactic acyclovir (or other antiviral agents) for patients being treated with bortezomib or bortezomib-based therapies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 5
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 50, No. 7 ( 2009-01), p. 1096-1101
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2009
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  • 6
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4947-4947
    Abstract: Abstract 4947 Background Recent advances in the treatment of multiple myeloma (MM) have significantly improved overall survival. With MM patients living longer, there is a constant need to find better therapeutic options, especially when patients are refractory to conventional agents, and are not eligible for experimental therapeutics in clinical trials. We evaluated treatment with single-agent high-dose cyclophosphamide (HDCy) in a cohort of heavily pre-treated patients with relapsed/refractory MM. Methods All the patients were previously treated for active MM at the University of Southern California (USC), Los Angeles, CA. Cyclophosphamide was administered at 1.2 gm/m2 in D5W intravenous (IV) over 1 hour every 3 hours for a total of 4 doses. Mesna was given to prevent urinary adverse events from cyclophosphamide as 4 gm/m2 in 1000 ml D5W IV to run at 50 ml/hr for 20 hours, starting 15 minutes prior to the first dose of cyclophosphamide. Patients were given pre-medications with 5HT3 antagonists an steroids. Treatment was administered in the in-patient setting and patients were discharged after the last dose of cyclophosphamide. Treatment was repeated every 4 weeks, if well-tolerated and continued response. Growth factor support was provided to the patients, as needed. Response to treatment was assessed after each 4-week cycle according to the International Uniform Response Criteria for MM. Results Seven patients (4 females, 3 males) were treated on this regimen with a median age of 53 years (range 34-61 yrs). These patients included 3 Hispanics (43%), 2 Asians (29%), 1 Caucasian (14%) and 1 African-American (14%). MM subtype was IgG disease in 3, IgA in 2, and light-chain only in 2 patients. Advanced stage disease ( 〉 stage 1) at the time of diagnosis as per the Durie Salmon (DS) staging system was present in 71% of the patients, while 3 patients (43%) had advanced stage disease as per the International Staging System (ISS). Four patients (57%) had lytic bone disease at the time of diagnosis, while only 1 patient was a non-secretor. Five of these patients (71%) never received an autologous stem cell transplant (ASCT) as a part of their MM treatment. Median number of therapies in these patients was 5 (range 4-8), while median number of therapies prior to high-dose cyclophosphamide (HDCy) were 3 (range 2-7). Median number of cycles of HDCy administered to the patients was 2 (range 1-5). Overall Response Rate (ORR = CR+PR) was 29% (n=2) with 1 patient achieving CR and 1 patient achieving VGPR. Four patients (57%) had stable disease (SD) and 1 patient had progressive disease (PD). Thus, the overall clinical benefit (CR+PR+SD) was seen in 6 out of the 7 patients (86%). Median time to best response was 5 weeks (range 4-10 weeks). Median time to progression was 16 weeks (range 8-24 weeks). Most common adverse events were cytopenias and fatigue, but were easily manageable with supportive care on an out-patient basis. Conclusions Despite improvement in therapeutic regimens for MM, it remains an incurable disorder. There is a constant need to develop regimens for treatment of relapsed/refractory MM patients that are efficacious and well-tolerated. We report the use of single-agent HDCy in heavily pre-treated MM patients. Despite the small number of patients studied, we have noted meaningful clinical benefit with a manageable toxicity profile. This warrants further investigation into developing therapeutic regimens with high-dose cyclophosphamide. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 7
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 1477-1477
    Abstract: Background: Renal dysfunction is a common consequence of MM. Patients can present with varying degrees of renal impairment during the course of their disease. Clinical management of these patients remains a challenge and the role of newer agents like bortezomib is still being defined in them. We have previously reported on the safety and efficacy of bortezomib in MM patients with advanced renal failure requiring dialysis. Here we further evaluate if varying degree of renal dysfunction as determined by the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF K/DOQI), adversely affects the clinical outcome of bortezomib-based therapies. Methods: All MM patients treated with bortezomib or bortezomib-based therapies were evaluable for this analysis. Response to treatment was classified as per EBMT criteria. Renal function stratification was done for all the patients based on NKF K/DOQI guideline stages as per glomerular filteration rate (GFR; ml/min/1.73 m2). Stages 1, 2, 3, 4 and 5 were defined as GFR ≥ 90, 60–89, 30–59, 15–29, and & lt; 15/dialysis, respectively. To study the statistical relationship between pairs of nominal variables, Fisher’s exact test was used. To study the statistical relationship between nominal and ordinal variables, exact Wilcoxon test was used. A 0.05 nominal significance level was used in all testing. Results: Sixty six consecutive patients were evaluable. Amongst these, 32 (48.5%) were females and 34 (51.5%) males with a median age of 59.5 years (range 40–82 years). Fifty five (83%) patients had advanced MM; stage & gt; I as per Durie-Salmon (DS) criteria. Eligible patients had either relapsed/refractory disease (n=33) or were previously untreated (n=33). NKF K/DOQI renal function stages were 1, 2, 3, 4 and 5 in 9 (13.6%), 29 (44%), 22 (33.4%), 3 (4.5%) and 3 (4.5%) patients, respectively. Clinical response observed was complete remission (CR) in 8 (12%), partial remission (PR) in 25 (38%), stable disease (SD) in 27 (41%) and progressive disease (PD) in 6 (9%) patients. There was no significant association between renal function and patient age (p = 0.0808; 95% CI -0.0246, 0.4367), DS stage (p = 0.1722; 95% CI -0.0806, 0.4744), Ig type (p = 0.5288), untreated vs. relapsed/refractory disease (p = 0.1352), or response to treatment (p = 0.5292; 95% CI -0.1601, 0.3114). Conclusions: In this paper we investigated the correlation of NKF K/DOQI renal function stage in myeloma patients with clinical response to bortezomib. We noted that patients treated with bortezomib-based therapies experienced similar clinical benefit irrespective of the NKF K/DOQI renal function stage. These findings further support our previous observation that bortezomib is an effective therapeutic option for MM patients with renal dysfunction. Best Response to Treatment in Each NKF K/DOQI Stage Stage Best Response To Treatment NKF K/DOQI; National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative, PD; Progressive Disease, SD; Stable Disease, PR; Partial Remission, CR; Complete Remission PD SD PR CR Total 1 1 3 4 1 9 2 3 14 10 2 29 3 2 6 9 5 22 4 0 1 2 0 3 5 0 3 0 0 3 Total 6 27 25 8 66
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 8
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2008
    In:  Journal of Clinical Oncology Vol. 26, No. 19 ( 2008-07-01), p. 3289-3290
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 26, No. 19 ( 2008-07-01), p. 3289-3290
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2008
    detail.hit.zdb_id: 2005181-5
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  • 9
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 1498-1498
    Abstract: Background: Overexpression of bcl-2 gene mediated by t(14;18) (q32;q21) results in increased transcription of the anti-apoptotic bcl-2 protein. This is associated with aggressive clinical behavior, resistance to conventional chemotherapy regimens and poor survival in multiple myeloma (MM) patients. Impact of novel therapeutic agents such as bortezomib has not been studied in context with this adverse molecular marker. Thus we investigated the clinical efficacy of bortezomib in MM patients who were positive for bcl-2 translocation. Methods: All MM patients treated with bortezomib or bortezomib-based therapies were evaluable for this analysis. bcl-2 translocation was studied by a nested PCR-based assay of patient bone marrow samples. The test is reproducibly sensitive to a detection level of 1:100,000 and reported as positive or negative, indicating either the presence or absence of t(14;18). Response to treatment was classified as per EBMT criteria. To study the statistical relationship between pairs of nominal variables, Fisher’s exact test was used. To study the statistical relationship between nominal and ordinal variables, exact Wilcoxon test was used. A 0.05 nominal significance level was used in all testing. Results: Sixty six patients met the inclusion criteria of MM diagnosis and treatment with bortezomib-based regimens. Of these, bcl-2 analysis was available for 41 patients. Six patients (14.6%) were bcl-2 positive and 35 (85.4%) were bcl-2 negative. Median age was 61 years (range 40–80 years), with 18 (43.9%) females and 23 (56.1%) males. Twenty three patients (56.1%) had Durie-Salmon (DS) stage IIIA disease. Lytic bony lesions were present in 31 (75.6%) patients and most common Ig type was IgG kappa (43.9%). Seven patients (17%) achieved CR, 14 (34%) had PR, 16 (39%) had stable disease (SD) and 4 (10%) had progressive disease (PD). There was no significant association found between t(14;18) result and patient age (p = 0.4985), gender (p = 0.6786), DS stage (p = 0.6117), ISS stage (p = 0.5541), presence of bony lytic lesions (p = 0.1435), patients being paraprotein secretors or non-secretors (p = 1), Ig type (p = 0.0584), or response to treatment (p = 0.1066). Conclusions: Presence of bcl-2 translocation is associated with aggressive clinical course and suboptimal response to conventional chemotherapy in myeloma patients. Although, the number of patients analyzed in this analysis is small, we did not find the presence of bcl-2 translocation to be an adverse prognostic marker in myeloma patients treated with bortezomib-based regimens.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
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  • 10
    Online Resource
    Online Resource
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 4274-4274
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4274-4274
    Abstract: Abstract 4274 INTRODUCTION Imatinib mesylate, an inhibitor of the BCR-ABL fusion protein, serves as the current standard of care in the treatment of chronic myeloid leukemia (CML). Since its introduction, significant improvements have been seen in both the course and prognosis of CML. Although imatinib is highly effective in treating CML, recent studies have demonstrated that approximately 30% of patients discontinue imatinib for at least 30 days during their first year of therapy. Clinically, treatment non-adherence is a common reason patients experience suboptimal outcomes and it has therefore become important to establish methods to predict compliance. Based on the association of treatment response with adherence, plasma imatinib levels can be used to predict compliance. METHODS A retrospective analysis was conducted on 19 CML patients (female 5, male 14; median age= 45.3) who received imatinib treatment at LAC+USC Medical Center. Patient charts, laboratory reports and physical examination reports were assessed and plasma concentrations were measured: 1) using liquid chromatography and 2) tandem mass spectrometry. A comparison was then made between Imatinib levels and CCyR. Compliance with imatinib therapy was assessed by chart review and patient history. RESULT: Nineteen patients were analyzed in this study: 1(5%), 17 (90%), and 1 (5%) were treated with 300, 400 and 600 mg imatinib daily, respectively. Fifteen (79%) were Hispanic, 4(21%) were previously treated with interferon, most patients (95%) were in chronic phase when they were diagnosed except one who was in accelerated phase. The median duration of imatinib therapy at the time of plasma imatinib testing was 37 months. The mean and SDs of trough plasma imatinib level was 1362 ng/ml and789 ng/ml, respectively. We found that the imatinib trough concentration was higher in our analysis compared to those reported in the IRIS study and the French group studies, 969 ng/ml and 1058 ng/ml respectively. The patients were divided into two groups (Q1–Q2) based on their imatinib trough level. The average of trough level of the first group (Q1) was 780 ng/ml (±230) (n=9), and that of the second group (Q2) was 1885 ng/ml (±746) (n=10). In total 67% (6 out of 9) of the patients in the first group (Q1) and 20% (2 out of 10) of patients in the second group (Q2) had poor compliance, demonstrating a significantly better compliance in the Q2 (P=0.0001). In terms of their response rate to treatment, Of the 17 patients, a total of 11 achieved a CCyR at 18 months (65%): 63% (5 out of 8) in Q1; 67% (6 out of 9) in Q2. There was no significant correlation between plasma imatinib level and response rate. However, there was a significant correlation between the compliance and the response rate. 80% (8 out of 10) of patients who were adherent to the treatment had CCyR at 18 months, compared to only 43% (3 out of 7) of patients who had CCyR at 18 months in the non-adherent group. (P value=0.0001). Conclusions: Non-adherence to imatinib therapy is common in CML patients and is associated with suboptimal response. Non-compliance should be considered as a possible reason for a patient's poor response to imatinib, prior to considering the patient as imatinib-resistant. Plasma imatinib level can be used as one of the tools to predict compliance. By examining patients' plasma imatinib level, it was shown that high imatinib plasma levels point to a higher likelihood of compliance, and low levels predict a lower likelihood of compliance. Disclosures: Gorospe: Novartis: Honoraria, Speakers Bureau. Yang:Novartis: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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