scholarly journals Indoleamine 2,3-Dioxygenase (IDO1) Levels and Activity Are Increased in Early Chronic Phase Chronic Myelogenous Leukemia (CML-CP) and Correlate with Molecular Response to Nilotinib Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1912-1912
Author(s):  
Sieghart Sopper ◽  
Satu Mustjoki ◽  
Gunther Gastl ◽  
Zlatko Trajanoski ◽  
Frank Giles ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Immune Evasion ◽  
Research Funding ◽  
Cell Activation ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Solid Cancer ◽  
Molecular Response ◽  
Inflammatory Status ◽  
Infection And Inflammation

Abstract Introduction:Indoleamine 2,3 dioxygenase (IDO1) is the rate-limiting enzyme during metabolism of the essential amino acid tryptophan (TRP). IDO1 is up-regulated mainly by interferons during infection and inflammation and depletes tryptophan, which results in reduced T cell activation and proliferation as well as expansion of immunosuppressive regulatory T cells. Deregulation of IDO1 activity has been implicated in cancer immune evasion, but its role in chronic phase (CP) CML remains elusive so far. Methods:A large panel of circulating pro-inflammatory cytokines and components of the IDO-pathway (soluble IDO1=sIDO1 and kynurenine/tryptophan ratio=KYN/TRP as a product of IDO1 activity) as well as plasmacytoid dendritic cells (pDC) were analyzed alongside the prospective pan-european ENEST1st clinical study (NCT01061177). This substudy included 52 nilotinib-naïve chronic phase (CP)-CML patients that were subsequently treated with 300 mg BID nilotinib and analyzed at months 6 and 12. Molecular responses were quantified in central EUTOS reference laboratories. Results: Soluble IDO (sIDO1) levels and KYN/TRP ratio are significantly up-regulated in newly diagnosed CP-CML and significantly drop during nilotinib therapy. sIDO1 levels significantly correlate with increased KYN/TRP, suggesting increased IDO1 activity at diagnosis. Increased sIDO is linked to a pro-inflammatory status in CML patients, as it positively correlates to increased serum neopterin levels as well as to various other pro-inflammatory markers, such as IFN-g, IL-8, IL-10, IL-17A, sVEGF-A, sVCAM-1 and sTNFR-1. Interestingly, albeit being an IFN-regulated gene, IDO1 activity (KYN/TRP) negatively correlated with the proportion of pDC, the main producers of IFN-a. Interestingly, a higher KYN/TRP is linked to superior molecular response, as demonstrated by a significant correlation of the KYN/TRP ratio to BCR-ABL transcript levels. Patients having a high KYN/TRP ratio (> mean +2SD of post therapy levels) reach deep molecular response rates (i.e. MR4.5) significantly earlier and at higher rates. Conclusions: CML diagnosis in CP is linked to an inceased inflammatory status, as shown by increased levels of sIDO and its metabolites kynurenine leading to an increased KYN/TRP ratio. In solid cancer increased IDO expression/activity is linked to inferior outcome by favoring immune evasion. In contrast, in CML an increased KYN/TRP ratio is associated with improved molecular outcome during nilotinib 1st-line therapy. One reason could be that IDO activity may reflect endogenous IFN-α production, a known factor favoring immune-mediated CML-control. Disclosures Sopper: Novartis: Other: Travel costs reimbursement. Mustjoki:BMS, Novartis, Pfizer: Consultancy, Honoraria, Research Funding. Gastl:Novartis: Consultancy, Research Funding. Giles:Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Janssen:BMS: Honoraria; Pfizer: Honoraria; ARIAD: Consultancy; Novartis: Research Funding.

scholarly journals Discontinuation of Dasatinib after Deep Molecular Response for over 2 Years in Patients with Chronic Myelogenous Leukemia and the Unique Profiles of Lymphocyte Subsets for Successful Discontinuation: A Prospective, Multicenter Japanese Trial (D-STOP Trial)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 791-791 ◽  
Author(s):  
Takashi Kumagai ◽  
Chiaki Nakaseko ◽  
Kaichi Nishiwaki ◽  
Chikashi Yoshida ◽  
Kazuteru Ohashi ◽  
...  
Keyword(s):  
Research Funding ◽  
Lymphocyte Subsets ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Consolidation Therapy ◽  
Cd8 Cells ◽  
Stop Trial ◽  
Significant Difference ◽  
Group B

Abstract Introduction The tyrosine kinase inhibitor (TKI), imatinib, dramatically improves the prognosis of chronic myelogenous leukemia (CML) by suppressing the function of BCR-ABL gene. It was shown that imatinib could be discontinued in a proportion of patients with CML who maintained deep molecular response (DMR) for at least 2 years. (Lancet Oncol. 2010; 11:p1029) Treatment with second generation TKI, dasatinib, after imatinib resistance/intolerance could also be discontinued after maintaining DMR for over 1 year in a proportion of patients with CML (Lancet Haematol. 2015; 2:p528). In this Japanese prospective multicenter trial (D-STOP trial by Shimousa Hematology and Kanto CML Study Groups, ClinicalTrials.gov Identifier: NCT01627132), we aimed to discontinue dasatinib in patients with CML who maintained DMR for over 2 years. Methods: Chronic phase CML patients treated with TKIs who had undetectable BCR-ABL1 mRNA were enrolled. After confirmation of undetectable BCR-ABL1 mRNA (International Scale <0.01%) using real-time quantitative polymerase chain reaction (RQ-PCR) in the central laboratory, the patient received additional dasatinib treatment for another 2 years as consolidation therapy. Patients who maintained DMR during the consolidation therapy proceeded to discontinue dasatinib. BCR-ABL1 mRNA was monitored every month in year 1 and every 3 months in year 2. Molecular relapse was defined as two successive positive RQ-PCRs for BCR-ABL1 within 1 month. The relapsed patients restarted dasatinib. The primary endpoint was treatment-free survival after 12 months of discontinuation. Lymphocyte subsets were analyzed using flow cytometry during and after the consolidation therapy. Results: Sixty-five patients received consolidation therapy, and 54 discontinued dasatinib treatment after maintenance of DMR for 2 years. Mean age of the patients was 54.2 (25-82) years, and median follow-up period after cessation of dasatinib was 16.2 (7-30) months. Twenty patients relapsed during the observation period. Using Kaplan-Meier analysis, the estimated overall treatment-free survival (TFS) was 62.9% (48.5-74.2) at 12 months (Fig.1). Most relapses occurred within 6 months after discontinuation of dasatinib. All relapsed patients responded again to dasatinib. There was no significant difference either in estimated TFS between males and females or Sokal scores at diagnosis. During the consolidation therapy, the proportion (%) of CD4+CD8−, CD3−CD56+, CD16+CD56+, and CD57+CD56+ cells among total lymphocytes were monitored using flow cytometry in patients who could discontinue dasatinib during the observation periods (group A) and those who relapsed (group B). At the start of the consolidation therapy, there was no significant difference between groups A and B (CD4+CD8−%: 33.6 vs 34.0, p = 0.89, CD3−CD56+%: 24.3 vs 24.1, p = 0.95; CD16+CD56+%: 22.1 vs 23.9, p = 0.57; CD57+CD56+%: 19.7 vs 21.8, p = 0.51, respectively). In group B, the proportion of CD4+CD8− cells gradually decreased, whereas CD3−CD56+, CD16+CD56+, and CD57+CD56+ cells gradually increased during the consolidation therapy. All four types of cells were relatively stable in group A. At the end of the consolidation therapy, there was a significant group difference in the proportion of these subsets (CD4+CD8−%: 29.6 vs 22.2, p = 0.018*; CD3−CD56+%: 25.9 vs 37.3, p < 0.01*; CD16+CD56+%: 23.2 vs 34.4, p < 0.01*; CD57+CD56+%: 21.9 vs 32.1, p < 0.001*; respectively). We concluded that patients with CD4+CD8− cells ≥23.1%, CD3−CD56+ cells ≤40.1%, CD16+CD56+ ≤35.6% or CD57+CD56+ ≤26.6% at the end of the consolidation therapy had significantly higher estimated overall TFS at 12 months than those without each condition (CD4+CD8−%: 84% vs 32%, p < 0.0001* (Fig.2); CD3−CD56+%: 77% vs 25%, p < 0.001* (Fig.3), CD16+CD56+%: 77% vs 25%, p < 0.0001*; CD57+CD56+%; 84% vs 46%, p < 0.01*, respectively). Although increased large granular lymphocytes and NK cells were reported to be associated with high responses to dasatinib (Int J Hematol. 2014; 99:p41), the unique profiles of lymphocyte subsets could predict successful discontinuation of dasatinib. Conclusion: Discontinuation of TKI in patients with chronic phase CML after consolidation therapy with dasatinib for 2 years was feasible with relatively high TFS. The unique profile of lymphocyte subsets might be able to predict successful discontinuation. Disclosures Kumagai: Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Nakaseko:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Pfizer: Honoraria, Research Funding. Nishiwaki:Novartis: Research Funding. Yoshida:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Morita:Bristol-Myers Squibb: Speakers Bureau. Sakamoto:Takeda Pharmaceutical: Consultancy; Yakult: Other: Remuneration. Inokuchi:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria; Pfizer: Honoraria.

Analysis of Molecular Data and the Emergence of Mutations for Chronic-Phase Chronic Myelogenous Leukemia (CML-CP) Patients Treated with Dasatinib After Imatinib Failure.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3282-3282
Author(s):  
Susan Branford ◽  
Andreas Hochhaus ◽  
Martin Mueller ◽  
Erkut Bahceci ◽  
Lynn Ploughman ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Second Line ◽  
Imatinib Resistance ◽  
Mutation Status ◽  
New Mutations

Abstract Abstract 3282 Poster Board III-1 The kinase inhibitor dasatinib has demonstrated efficacy in patients with CML-CP who fail imatinib due to resistance or intolerance. Imatinib failure is often associated with the acquisition of resistant mutations within BCR-ABL. Failure of dasatinib is associated with a limited spectrum of mutations, which are T315I/A, V299L, and F317L/I/V, suggesting these mutations are dasatinib resistant (DR). Only a fraction of patients with T315I respond to dasatinib, most patients with F317L have hematologic responses but few have cytogenetic responses, and V299L is uncommon in imatinib-resistant patients but is mostly seen after dasatinib failure. In vitro data suggests Q252H and E255K/V also confer a degree of dasatinib resistance. However, their clinical association with dasatinib resistance or inferior response is unclear. This retrospective analysis seeks to determine if the mutation status at the start of dasatinib impacts the initial molecular response, and to examine the type of mutations lost and gained during therapy. To assess the significance of intermediate sensitivity (DI) mutations (Q252H and E255K/V), BCR-ABL levels were measured against the International Scale (IS), and mutation status was assayed at initiation of dasatinib (baseline), at progression, or study termination or completion (progression/completion). Data were taken from 479 patients with CML-CP treated with dasatinib 70 mg twice daily, after imatinib failure for the phase II START-C or -R studies. Patients were grouped according to their baseline mutation status: DR, DI, dasatinib sensitive (DS, all other mutations not DR or DI), and no mutations. Patients with more than one mutation at baseline that qualified for more than one grouping were rare, and classified according to the most resistant mutation. By 6 months of dasatinib therapy, patients with DR mutations at baseline had the highest levels of BCR-ABL transcripts (Table 1). By comparison, those with DI, DS, or no mutations had a reduced proportion with high transcript levels. In addition, no patients with DR at baseline achieved a reduction of BCR-ABL by 6 months to IS ratio < 1, whereas significant reductions were identified in patients with DI, DS, or no mutations. A subset of 267 patients had mutation analysis performed at progression/completion. Of these, 115 had mutations at baseline and 152 had no mutations. The patients with baseline imatinib resistance were more likely than those with imatinib intolerance to acquire new mutations. Of the resistant patients with no mutations at baseline, 7% (9/124) developed new mutations and the majority (7/9) was DR. Among resistant patients with baseline mutations, 23% (26/112) had new mutations and the majority was DR (20/26). Although 36 patients gained new mutations (including 16 T315I/A, 8 F317L, and 6 V299L), many baseline mutations were no longer detectable at progression/completion. DS mutations were lost in 68/102 patients. In total, 76 patients had detectable mutations at progression/completion, with 51% (39/76) having DR mutations but only 5% (4/76) with DI mutations. Patients with baseline DR mutations were more likely to retain their DR mutations (11/13). Of 8 patients with DI mutations at baseline, only 3 retained their DI mutations and 3 gained DR mutations. Of 94 patients with only DS mutations at baseline, 36 (38%) retained their DS mutations, and 17 (18%) developed DR mutations. Patients with high levels of BCR-ABL at 3 months had the highest incidence of new DR mutations at progression/completion (18/145 evaluable patients; 12%) compared to patients with lower levels (5/79; 6%). In conclusion, the development of new mutations during second-line dasatinib is rare (36/267). Patients who harbored DI mutations at baseline were also rare, and an expanded prospective analysis of dasatinib efficacy in this cohort may be necessary to clarify their significance. However, from the current analysis there is no compelling clinical evidence to suggest that these patients have an inferior molecular response. Relative to DR mutations, the DI mutations (Q252H and E255K/V) were rarely present at progression/completion. Patients with baseline mutations and 6-month BCR-ABL transcript level after second-line dasatinib IS ratio ≤ 1.0 1 < IS ratio ’ 10 IS ratio > 10 DR 0% (0/13) 23% (3/13) 77% (10/13) DI 56% (5/9) 0% (0/9) 44% (4/9) DS 36% (46/128) 20% (25/128) 45% (57/128) No mutations 42% (92/221) 18% (40/221) 40% (89/221) Disclosures: Branford: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Bahceci:Bristol-Myers Squibb: Employment. Ploughman:Bristol-Myers Squibb: Employment. Mukhopadhyay:Bristol-Myers Squibb: Employment. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding.

Clinical or Sub-Clinical Pancreatitis (PA) Associated with Nilotinib (Nb) As Frontline for Chronic Myelogenous Leukemia (CML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4443-4443
Author(s):  
Mahran Shoukier ◽  
Hagop M. Kantarjian ◽  
Elias Jabbour ◽  
Alfonso Quintas-Cardama ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Risk Factors ◽  
Tyrosine Kinase ◽  
Research Funding ◽  
Chronic Phase ◽  
Initial Therapy ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Close Monitoring ◽  
Pancreatic Cell ◽  
Free Survival

Abstract Abstract 4443 Background: Nilotinib is now standard therapy in chronic phase (CP) CML, both as initial therapy and after imatinib failure. One of the adverse effects of nilotinib is the increase in serum amylase and/or lipase levels with or without clinical pancreatitis.The mechanism by which nilotinib increases serum pancreatic enzymes is not clear. Nilotinib is able to inhibit the non-receptor tyrosine kinase c-abl with high affinity. It is possible that c-abl inhibition might interfere with the molecular mechanisms regulating pancreatic cell death, inducing pancreatic damage. Nilotinib may release calcium from the intracellular acinar stores which regulate exocrine pancreatic secretion, or it may promote the accumulation of fatty acid inside the pancreatic acinar cells which disturbs exocytose. (JOP. J Pancreas (Online) 2010 May 5; 291–293). Purpose: To understand the frequency, risk factors and management strategy for patients who develop pancreatitis (clinical or subclinical) during nilotininb frontline therapy for CML. Method: We reviewed the records of 105 CML patients treated at our institution on a clinical trial from 7/2005 to 7/2011 with nilotinib 400 mg twice daily as initial therapy for CML in chronic phase. Results: The median age for the total population was 52 yrs (range, 17 to 89), and 63 were males (60%). Thirteen (12%) pts experienced pancreatitis at least once, most frequently asymptomatic (ie, grade 1). Pancreatitis episodes occurred 28 times (2 episodes were grade 3, 2 episodes were grade 4, 10 episodes were grade 2, and 14 episodes were grade 1). Thirteen episodes (47%) occurred at a dose of 200 mg daily, 4 (14%) at 400 mg daily, and 11 (39%) at 800 mg daily. In 3 instances total bilirubin was also elevated (2 grade 2 and 1 grade 4). One patient experienced recurrent elevations (16 episodes) of lipase and amylase despite dose reduction to 200mg once daily. Concurrent use of hydrochlorothiazide and moderate alcoholic intake were identified as risk factors associated with pancreatitis in the patient who experienced recurrent episodes. Diabetes was identified as a risk factor for pancreatitis in other 4 pts. Twenty four episodes (86%) were characterized by an elevation of lipase and amylase without any clinical symptoms. In four instances, patients experienced a moderate abdominal pain without other symptoms of pancreatitis. In 3 instances, imaging (ultrasound and/or CT scan) demonstrated normal pancreases. Management of pancreatitis included transient nilotinib interruption in most instances. In most patients, lipase and amylase values returned to normal within 14 days of stopping nilotinib. Three patients eventually required change from nilotinib to other tyrosine kinase inhibitors (TKI) (imatinib 2, dasatinib 1) without recurrence of pancreatitis. One of these pts switched to imatinib because of recurrent pancreatitis and the other 2 were switched because of nilotinib toxicities (liver and cardiac toxicity). At the time of pancreatitis episodes, 54% had achieved complete cytogenetic response (CCyR), and 8% complete molecular response (CMR). Rates of (CCyR) were 92% and 94% in patients who experienced and who did not experience pancreatitis, respectively. Rates of major molecular response (MMR) were 100%and 87% in patients who experienced and who did not experience pancreatitis, respectively. Rates of complete hematologic response (CHR) were 100% and 98% in patients who experienced and who did not experience pancreatitis, respectively. The 3-year event-free survival (EFS), treatment- free survival (TFS), and overall survival (OS) rates were 100% in patients who experienced and 93%, 97%, and 100% in patients who did not experience pancreatitis, respectively. Conclusion: Pancreatitis associated with nilotinib is most frequently grade 1 and 2 (asymptomatic enzyme elevation). Close monitoring and timely intervention may allow patients to continue therapy and achieve the desired clinical benefit. Rarely, pancreatitis may require treatment discontinuation. Disclosures: Cortes: BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Deciphera: Research Funding.

Loss Of Major Molecular Response As a Trigger For Restarting Tyrosine Kinase Inhibitor Therapy In CP-CML Patients Who Have Stopped Imatinib After Durable Undetectable Minimal Residual Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 381-381 ◽  
Author(s):  
Philippe Rousselot ◽  
Aude Charbonnier ◽  
Pascale Cony-Makhoul ◽  
Philippe Agape ◽  
Franck E Nicolini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Chronic Phase ◽  
Lymphoid Cells ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Advisory Committees ◽  
Number Of Patients

Abstract Purpose More than half of patients with chronic phase chronic myelogenous leukemia (CP-CML) in complete molecular response (CMR) experience molecular relapse after imatinib discontinuation. We investigated loss of major molecular response (MMR) as a criterion for resuming therapy. Patients and methods A multicenter observational study (A-STIM, According to STop IMatinib) evaluating MMR persistence was conducted in 80 CP-CML patients who had stopped imatinib after prolonged confirmed CMR (24 months or more). Patients with confirmed CMR with 1 or 2 occasional weak positive samples before study entry were also considered eligible. CMR was defined as undetectable BCR-ABL transcript with a sensitivity of at least 40000 amplified copies of the ABL control gene, in accordance with the level of sensitivity routinely applied within laboratories participating in the French GBMHM Network. Results Median time from imatinib initiation to discontinuation was 79 months (range 30-145), median duration of CMR before imatinib discontinuation was 41 months (24-96), and median follow-up after discontinuation was 31 months (8-92). Twenty-nine patients (36%) lost MMR after a median of 4 months off-therapy (2-17). Cumulative incidence of MMR loss was estimated as 35% (95% CI, 25%-46%) at 12 months and 36% (95% CI, 26%-47%) at 24 months whereas probability of losing CMR was estimated as 51% at 12 months (95% CI, 41%-63%) and 54% at 24 months (95% CI, 44%-66%). Fivety two percent of the patients met the criteria for cCMR but experienced occasional BCR-ABL positivity (unstable cCMR). Those patients were not at higher risk of losing MMR as compared to patients with stable cCMR. This observation may potentially increase by two-fold the number of patients eligible for TKI discontinuation. Fluctuation of BCR-ABLtranscript levels below the MMR threshold (≥ 2 consecutive positive values) were observed in 31% of patients after imatinib discontinuation. Using cell sorting in three fluctuating patients, we were able to confirm that BCR-ABL signal was mostly present in the CD15 positive fraction, demonstrating first that BCR-ABL residual signal was not related to long living lymphoid cells and second that residual CML cells retain a clonogenic potential. Treatment-free remission was estimated as 64% (95% CI, 54%-75%) at 12 and 24 months and 61% (95% CI, 51%-73%) at 36 months. Treatment was resumed in 31 patients after loss of MMR. Twenty-three patients regained CMR4.5 and 8 patients are in MMR under therapy after 2+ to 17+ months. Median to time to a second CMR was estimated as 7.3 months in retreated patients. Conclusion The probability of losing MMR after imatinib discontinuation was estimated as 36% in the long-term. Loss of MMR is a practical and safe criterion for restarting therapy in CML patients with prolonged CMR and could be used for future discontinuation studies. Disclosures: Rousselot: Novartis: Research Funding; BMS: Research Funding. Cony-Makhoul:BMS: Honoraria; Novartis: Research Funding. Nicolini:BMS, Teva, Ariad, Pfizer, Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Etienne:Novartis: Consultancy; Pfeizer: Consultancy; Novartis: Honoraria; BMS: Honoraria. Guerci-Bresler:Novartis: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees. Turhan:BMS: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; BMS: Honoraria; Novartis: Research Funding. Guilhot:BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Pfizer: Consultancy; BMS: Research Funding; Novartis: Research Funding. Mahon:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Brisol Myers Squibb: Consultancy, Honoraria; Ariad: Honoraria; Pfizer: Honoraria.

ENESTPath: A Phase 3 Study to Assess the Effect of Nilotinib Treatment Duration on Treatment-Free Remission (TFR) in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with Imatinib: 24-Month Analysis of the First 300 Patients in the Induction/Consolidation Phase

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3094-3094 ◽  
Author(s):  
Delphine Rea ◽  
Gianantonio Rosti ◽  
Nicholas CP Cross ◽  
Andrzej Hellmann ◽  
Dietger Niederwieser ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Research Funding ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Low Grade ◽  
Molecular Response ◽  
Current Recommendation ◽  
Phase 3 ◽  
Consolidation Phase ◽  
Grade 3

Abstract Background Tyrosine kinase inhibitors (TKIs) are the standard of care for patients (pts) with CML-CP. The current recommendation is to continue TKI therapy indefinitely.1 Results of several clinical trials indicate that pts achieving sustainable deep molecular response (DMR; defined as molecular response ≥ MR4) on imatinib (IM) may achieve long-lasting TFR. Nilotinib (NIL) at 300 mg bid induces higher rates of DMRs compared to IM.2 Also, DMRs can be achieved in pts with NIL (400 mg bid) who are switched after long-term IM.3 However, the optimal duration of consolidation treatment with NIL to increase the chances for successful and continuous TFR (≥ MR4) after stopping treatment is not yet known. Objective ENESTPath was designed to assess the proportion of pts (pretreated with IM and subsequently treated with NIL 300 mg bid) who can achieve a sustained DMR and maintain TFR without relapse for 12 months (mo) upon treatment discontinuation after different durations of treatment in consolidation phase. Methods ENESTPath is a randomized, phase 3 study enrolling pts with CML-CP who achieved a complete cytogenetic response (CCyR), but not MR4, after at least 24 mo of treatment with IM. After enrollment, pts were assigned to receive NIL at 300 mg bid for either 24 mo or 36 mo (arm 1 and arm 2, respectively). Pts with stable MR4 or better for at least 12 mo will enter the TFR phase. A stable MR4 was defined by 4 of the 5 preceding quarterly real-time quantitative RT-PCR (RQ-PCR) assessments ≥ MR4 and ≥ MR4 inthe last assessment performed by IS certified EUTOS laboratories. Results A total of 619 pts were enrolled in the study between May 2013 and June 2015. The present analysis reports the results of the first 300 pts (mean age, 50.8 years; 63.7% of males) enrolled and treated with NIL for 24 mo in induction and consolidation phase or who had discontinued earlier. Details of the baseline characteristics are given in Table 1. At data cutoff, 108 pts were in stable MR4; 101 (33.7%) were randomized and 7 (2.3%) were scheduled for randomization at that time point. 192 pts (64%) were not eligible for randomization, primarily due to lack of stable MR4 in 126 pts (42%), adverse events (AEs) or abnormal laboratory values in 44 pts (14.7%), and for other reasons in 22 pts (7.3%). The rates of MR4 at baseline*, 6 mo, 12 mo, 18 mo, and 24 mo were 14.3%, 43.3%, 45.7%, 43.7%, and 46%, respectively. By 24 mo of treatment with NIL, cumulative incidences of major molecular response (MMR), MR4, and MR4.5 of all treated pts not in respective MR at baseline were 93.2%, 69.3% and 42.1%, respectively (Figure 1). Further analysis showed that pts with MMR at baseline had a higher probability of achieving an MR4 than those lacking MMR at baseline, with a cumulative incidence of MR4 by 24 mo of 75.8% and 44.2%, respectively. No new safety signals were observed during the 24 mo consolidation with NIL. The majority of the AEs were low grade. Most common AEs irrespective of the relationship to the study drug were pruritus (19%), hypercholesterolemia (14.0%), rash (10.7%), asthenia (10%), and arthralgia (10%). The most common newly occurring or worsening all-grade biochemistry laboratory abnormalities included increase in total cholesterol (68.7%), increased ALT (54%), hyperglycemia (32.7%), and hyperbilirubinemia (37%); majority of them were grade 1 and 2. Newly occurring or worsening all-grade cytopenias include anemia (12.7%), thrombocytopenia (2.3%), leukopenia (2%), and neutropenia (1%). Grade 3 or 4 cardiovascular events (CVEs) were experienced by 6.7% of pts including ischemic heart disease (4.7%), peripheral artery occlusive disease (1.7%), and ischemic cerebrovascular events (0.7%) (Table 2). Conclusions This analysis of the first 300 pts after 24 mo of NIL treatment showed a cumulative incidence of MR4 in ~ 70% of pts who were not in MR4 at baseline with an advantage in favor of MMR at baseline. 108 pts (36%) were with stable MR4 at data cutoff and 192 pts (64%) discontinued the study due to very stringent protocol definitions of eligibility for randomization and AEs. Grade 3 or 4 AEs were consistent with the previous reports.4 References 1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Myelogenous Leukemia V.1.2016 ©2016 National Comprehensive Cancer Network, Inc. 2. Hochhaus A, et al. Leukemia. 2016;30:1044-1054. 3. Hughes TP, et al. Blood. 2014;124:729-736. 4. Rea D, et al. Blood. 2015;125:[abstract 4040]. Disclosures Rea: Ariad: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Rosti:Roche: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Cross:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Niederwieser:Novartis: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. Pregno:Novartis: Honoraria; BMS: Honoraria; ARIAD: Honoraria. Orlandi:Ariad: Honoraria; BMS: Honoraria; Novartis: Honoraria. Almeida:Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Shire: Speakers Bureau; Alexion: Speakers Bureau. Illes:University of Debrecen faculty of medicine department of hematology: Employment. Sagues:ICO-Girona/hospital Universtiari de Girona Dr. Josep Trueta: Employment. Haenig:Novartis: Employment. Supekar:Novartis: Employment. Shah:Cognizant: Employment; Novartis: Other: Vendor. Saglio:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Steegmann:Aria: Honoraria, Other: Research funding for Spanish CML Group; BMS: Honoraria, Other: Research funding for Spanish CML Group; Novartis: Honoraria, Other: Research funding for Spanish CML Group; Pfizer: Honoraria, Other: Research funding for Spanish CML Group. Baccarani:Pfizer: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

Pegylated Interferon-α 2a in Combination to Nilotinib As First Line Therapy in Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia Provides High Rates of MR4.5. Preliminary Results of a Phase II Study.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 166-166 ◽  
Author(s):  
Franck E. Nicolini ◽  
Gabriel Etienne ◽  
Viviane Dubruille ◽  
Lydia Roy ◽  
Françoise Huguet ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Research Funding ◽  
Chronic Phase ◽  
Pegylated Interferon ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Front Line ◽  
Molecular Responses ◽  
Line Therapy ◽  
Grade 3

Abstract Abstract 166 Background Imatinib mesylate combined to pegylated interferon alfa 2a (Peg-IFN) has been reported to significantly enhance the molecular responses for de novo chronic phase chronic myeloid leukemia (CP-CML) patients compared to Imatinib alone in a Phase 3 study (Preudhomme et al. NEJM 2010). Second generation tyrosine kinase inhibitors (TKI2) such as nilotinib induce significantly higher levels of cytogenetic and molecular responses than imatinib as front line therapy for CP-CML (Saglio et al., NEJM 2010). Aims Test the combination of nilotinib + Peg-IFN as front line therapy in CP-CML patients in order to check the safety and evaluate the molecular response rates (EudraCT 2010–019786–28). Methods In this 2-step French national study, patients were assigned first to Peg-IFN (± HU) for a month at 90 mg/wk prior to a combination of nilotinib 300 mg BID + Peg-IFN 45 mg/wk for ≥ 1 year. The primary endpoint was the rate of confirmed (on 2 datapoints) molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised for all patients and expressed as BCR-ABLIS in %. Results In the first cohort, 40+1 patients (1 screen failure) were enrolled and a second cohort of 20 patients was planned once the last patient of cohort 1 attained 1 year of treatment, if the primary endpoint would have not been reached. The current median follow-up is 13.6 (10.1–16.3) months. Sokal and Euro scores were high for 12% and 2%, intermediate for 49% and 55% and low for 39% and 43% of the patients respectively. Euro score was high for one patient. The median age was 53 (23–85) years. Two patients had a masked Philadelphia chromosome, 3 a variant form, and 1 had additional chromosomal abnormalities, all patients had a “major” BCR transcript. Five percent of patients were in CHR at 1 month of Peg-IFN and 100% at month (M) 2 (after 1 month of combination therapy). The rates of Complete Cytogenetic Responses (CCyR) at 3, 6, and 12 months of combination (i. e. at 2, 5, 8 and 11 months of TKI2) were 47%, 71%, 100% respectively on evaluable samples. The incidence of molecular responses are mentioned in figure 1. Of note, 87% of the patients had a BCR-ABLIS ≤10% at M3. The rates of molecular responses broke down by major molecular response (MMR): 27%, 4 log reduction (MR4): 36%, and ≥4.5 log BCR-ABL reduction (MR4.5, MR5 and undetectable): 21% with a total number of 84% patients in ≥MMR and beyond (17.5% and 67.5% in intention-to-treat respectively) at 1 year. Confirmed molecular results at 1 year will be presented. Nilotinib trough levels centrally analysed at M3, 6 and 12 for the vast majority of patients were ≥ 1000 ng/ml and Peg-IFN did not seem to impact on its pharmacokinetics. One patient went on unmutated myeloid blast crisis at M6 and is alive after allogeneic stem cell transplantation. Four additional patients were withdrawn from study: At M2 for non observance, at M6 for seizures related to an extra-dural hematoma, at M6 for recurrent grade 3 hepatic toxicity, at M9 for recurrent grade 3 pruritus. The median dose of Peg-IFN delivered to the patients during the first month was 90 (0–180) mg/wk, 45 mg/wk at M2, 3, 9, 12, and 33.75 mg/wk at M6. The median doses of nilotinib delivered to the patients were 600 mg daily at M2, 3, 6, 9, 12 and 15 as initially planned. The rate of grade 3–4 hematologic toxicities overall were anemia 2.5%, thrombocytopenia 41%, neutropenia 41% and pancytopenia 5%. These were observed mainly during M2 (16% neutropenia, 24% thrombocytopenia, 3% anemia), M3 (16% neutropenia, 13% thrombocytopenia, 3% pancytopenia) and M6 (12.5% neutropenia, 5% thrombocytopenia) and disappeared thereafter. Grade 3–4 toxicities occurred mostly during the first 3 months with 15% cholestatic episodes, 5% of ALAT elevation, 2.5% of lipase elevation, 2.5% arthro-myalgias, 2.5% abdominal pain without lipase elevation, 2.5% of depression. No PAO was observed and, to date, no dyslipidemia. Conclusion The combination of nilotinib and Peg-IFN seems relatively well tolerated despite frequent initial and transient hematologic and hepatic toxicities, and provides very high rates of molecular responses at 1 year and beyond. According to the initial methodology of this trial, the second cohort of patients will not be enrolled as the MR4.5 rates at M12 are beyond the initial expectations. A randomised phase III study testing nilotinib versus nilotinib + Peg-IFN is warranted. Disclosures: Nicolini: Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Etienne:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy. Roy:Novartis, BMS: Speakers Bureau. Huguet:Novartis, BMS: Speakers Bureau. Legros:Novartis, BMS: Research Funding, Speakers Bureau. Giraudier:Novartis: Speakers Bureau. Coiteux:Novartis, BMS: Speakers Bureau. Guerci-Bresler:Novartis, BMS: Speakers Bureau. Rea:Novartis, BMS: Consultancy, Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Hermet:Novartis, BMS: Speakers Bureau. Rousselot:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy, Speakers Bureau. Guilhot:Novartis, Ariad, and BMS: Consultancy, Speakers Bureau. Mahon:Novartis, BMS: Consultancy, Speakers Bureau.

Pharmacologic Monitoring of Dasatinib As First Line Therapy in Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia (CP-CML) Identifies Patients At Higher Risk of Pleural Effusion: A Sub-Analysis of the OPTIM-Dasatinib Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3770-3770 ◽  
Author(s):  
Philippe Rousselot ◽  
Luigina Mollica ◽  
Gabriel Etienne ◽  
Stephane Bouchet ◽  
Agnès Guerci ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Research Funding ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
First Line ◽  
Group A ◽  
Group B

Abstract Abstract 3770 Background: Second generation tyrosine kinase inhibitors such as dasatinib (Sprycel®, Bristol-Myers Squibb) induce significantly higher levels of cytogenetic and molecular responses than imatinib when given as frontline therapy for chronic phase chronic myelogenous leukemia (CP-CML) (DASISION trial, Kantarjian et al., NEJM 2010). Dasatinib is associated with the occurrence of pleural effusions (PE). The cumulative incidence of all grades PE in DASISION trial was reported to be 10% by 12 months and 14% by 24 months. Aims: To analyse efficacy of dasatinib first line and to test risk factors associated with the occurrence of PE. (EudraCT 2008–006854–17). Methods: Newly diagnosed CP-CML patients (pts) were assigned to dasatinib 100 mg/d. Dasatinib Cmin levels were assessed 24+/−2h after intake by tandem mass spectrometry after 2 weeks of therapy and every 3 months during 12 months thereafter. Pts with high Cmin values (Cmin ≥ 3 nM) at day 15 were randomized between dasatinib dose reduction or not. As the trial is still recruiting, the effect of randomization (treatment adaptation) was not analysed. For the purpose of this study, patients with at least 12 months follow-up were analysed for efficacy and all enrolled patients were analysed for safety. Molecular assessments were expressed as BCR-ABL/ABL (IS) in %. Results: Efficacy. In March 2012, 125 pts out of 191 pts enrolled in the trial had at least 12 months follow-up. Sokal scores were high for 18%, intermediate for 36% and low for 46% of pts. The median age was 52 (18–89) years. The rates of complete cytogenetic responses (CCyR) at 3, 6, and 12 months were 74%, 87%, and 97% respectively on evaluable samples, and 60%, 82%, and 95% when results were analysed according to the intention-to-treat principle taking into account missing values. The cumulative incidences of major molecular response (MMR) by 3, 6, 9 and 12 months were 21%, 46%, 56%, and 62% respectively. Of note 11 pts (9%) did not have a BCR-ABL (IS) ≤10% at 3 months. None of these patients reached a MMR by 12 months compared to a 68% (95% CI: 60–77) cumulative incidence of MMR in the other 114 pts. At 12 months, molecular response 4.5 (MR4.5) rate was 25%, including 80% of the pts with undetectable BCR-ABL transcript (sensitivity 4 to 5 log). Safety. 12 pts out of 191 (6.3%) presented a PE corresponding to a cumulative incidence of 9% by 24 months. 95 pts had at least one high Cmin value during the pharmacokinetic follow-up and 10 pts developed PE as compared to 2 out of the 96 remaining pts (p= 0.018). Cumulative incidence of PE by 24 months was 13.4% in high Cmin group as compared to 4.8% in low Cmin group (p=0.04). We next analysed whether the measurement of dasatinib Cmin at day 15 could predict the risk to develop a PE. Fifty pts (26%) had a high Cmin value at day 15 (group A) and 141 had a low Cmin (group B). The cumulative incidence of PE by 24 months was 17.4% in group A compared to 6.9% in group B (p=0.021) (fig 1). We next search for clinical factors influencing Cmin value at day15 of dasatinib 100 mg/d. Median Cmin values were significantly higher in patients aged 50 and over as compared to younger patients (2.5 nM versus 1.6 nM, p=0.0032). As expected, age 50 and over was also associated with an increased risk of pleural effusion. Conclusion: Current data demonstrate efficacy of dasatinib 100 mg/d similar or even better to that reported in other frontline trials such as the DASISION trial. We provide evidences suggesting that a high Cmin (>3nM) at day 15 and/or age 50 and over identify patients treated with dasatinib 100 mg/d with a high risk of PE. The benefit of dasatinib dose reduction is randomly tested for this group of patients in the OPTIM-Dasatinib trial and may be a major issue in elderly patients. Disclosures: Rousselot: BMS, Novartis: Research Funding. Nicolini:BMS, Novartis: Consultancy, Research Funding. Coiteux:Novartis, BMS: Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Roy:Novartis, BMS: Speakers Bureau. Dartigeas:Roche: Consultancy. Guilhot:ARIAD: Honoraria. Mahon:Novartis Pharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy.

scholarly journals Which One, Generic Vs Original Glivec Is More Effective in Patients with Chronic Myeloid Leukemia?

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4156-4156
Author(s):  
Ekin Kircali ◽  
Guldane Cengiz Seval ◽  
Sinem Civriz Bozdag ◽  
Selami Kocak Toprak ◽  
Meltem Kurt Yuksel ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Research Funding ◽  
Chronic Phase ◽  
Response Rates ◽  
Molecular Response ◽  
Optimal Response ◽  
Generic Group ◽  
Significant Difference ◽  
Generic Groups ◽  
Support Research

Introduction:Generic imatinib formulations are increasingly being used as more affordable alternatives worldwide and a few studies have evaluated the safety and efficacy of these formulations prospectively. We have retrospectively analyzed our CML cohort in terms of first line treatment of Glivec versus generic imatinib. This study aims to evaluate the safety and efficacy of generic imatinib products in chronic phase chronic myeloid leukemia as first line treatment. Methods:We have retrospectively analyzed our CML cohort from January 2000 to December 2018 treated with either Glivec or one of generic imatinib formulations. All of our patients (with 1 exception) were initiated imatinib in chronic phase in less than 56 days from diagnosis. All of our patients were followed in accordance with European Leukemia Net (ELN) 2013 recommendations and national hematology association CML guidelines and response definitions were applied according to ELN 2013 criteria. Event free survival (EFS) was defined as the time between treatment initiation and either loss of hematological response, progression to accelerated phase (AP) or blastic phase (BP), or death from any cause. Progression free survival was defined as the time between treatment initiation and transformation to AP, BP or death while on imatinib. For statistical analyses SPSS version 21.0 was used. All p values < 0.05 were considered statistically significant. Results:A total of 192 patients were analyzed comparing 102 (53.1 %) patients on Glivec with 90 patients on (476.9 %) generic formulations. 99 (51.6 %) were female patients. The median age of our population was median 46 years (14-88 years) for Glivec and median 51 years (19-79 years) for generic group (p=0.01). Risk stratifications according to Sokal, Hasford and ELTS scores were run for both Glivec and generic formulation groups. Most of the patients had low risk according to Sokal (137, 71.4%) and Hasford (116, 60.4 %) but intermediate risk according to ELTS (113, 58.9 %) scoring systems. There was no statistically significant difference in the gender distribution, Sokal, Hasford, ELTS scores and ECOG between the two groups. The median time to initiate imatinib treatment was 23.5 (1- 156) days for Glivec group and 13 (1- 51) days generic group (p< 0.05). But the late onset of the treatment was not associated with treatment failure or death. The median follow up was 119.8 (3.7- 250.5) months for Glivec group and 43.6 (2- 150) months for generic groups, respectively (p< 0.05). This difference might be explained by the fact that Glivec has been on the market for about two decades. Similar rates of grade> 2 hematological and non- hematological toxicity were seen in Glivec (4.9 %) and generic groups (3.3 %), respectively (p> 0.05). The rates of treatment failure at 3 months were significantly higher in generic formulation (6.7 %) group than Glivec (2.9 %) group (p< 0.05). Also, the rates of treatment failure at 6 months were significantly higher in generic formulation (3.3 %) group than Glivec (0.9 %) group (p< 0.05). Optimal molecular response rate at 3 months was 76.5 % (n=78) for Glivec and 32.2 % (n=29) for generic groups (p< 0.001). Also, optimal molecular response rate at 6 months was 69.6 % (n=71) for Glivec and 45.6 % (n=41) for generic groups (p= 0.01). Median EFS was found significantly higher for Glivec group compared to generic group (168 mos (95% CI: 159-177 mos) vs 74.6 mos (95% CI: 56-93); p<0.001) (Figure). Conclusion: We found that complete hematological response rates at 3 and 6 months were similar in both groups, but in early phase of treatment the optimal response rates of Glivec group was statistical significantly higher than generic group. Generic group presented with a lower rate of optimal response at 3 months but 13.4 % improvement in optimal response rates was observed at six months. No significant difference in safety concerns was observed between the groups. We recommend that these results from single center should be clarified in a prospective, randomized study including larger population. Figure Disclosures Özcan: AbbVie: Other: Travel support, Research Funding; MSD: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Other: Travel support; BMS: Other: Travel support; Jazz: Other: Travel support; Sanofi: Other: Travel support; Abdi Ibrahim: Other: Travel support; Janssen: Other: Travel support, Research Funding; Bayer: Research Funding; Celgene Corporation: Research Funding, Travel support; Takeda: Honoraria, Other: Travel support, Research Funding; Archigen: Research Funding; Roche: Other: Travel support, Research Funding. Beksac:Celgene: Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Clinical Importance of Drug Adherence during Tyrosine Kinase Inhibitor Therapy for Chronic Myelogenous Leukemia in Chronic Phase

2019 ◽  
Author(s):  
Yasuhiro Maeda ◽  
Atsushi Okamoto ◽  
Kenta Yamamoto ◽  
Go Eguchi ◽  
Yoshitaka Kanai
Keyword(s):  
Tyrosine Kinase ◽  
Second Generation ◽  
Adverse Drug Events ◽  
Kinase Inhibitor ◽  
Myeloproliferative Neoplasm ◽  
Clinical Importance ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Drug Adherence

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm constituting approximately 15% of newly diagnosed leukemia in adult patients. Development of tyrosine kinase inhibitors (TKIs) have dramatically improved outcomes in patients with chronic CML in chronic phase. However, adverse drug events (ADEs) associated with TKI therapy have influenced drug adherence, resulting in adverse clinical outcomes and a decline in the quality of life (QoL). In this study, we carried out a unique questionnaire survey to evaluate ADEs, which comprised 14 adverse events. We compared drug adherence rates between patients using imatinib and those who switched from imatinib to nilotinib, a second-generation TKI. Following the switch, the total number of ADEs decreased considerably in most cases. Simultaneously, better QoL was observed in the nilotinib group than in the imatinib group. Drug adherence was measured using Morisky&rsquo;s 9-item Medication Adherence Scale (MMAS). MMAS increased significantly after switching to nilotinib in all cases. Drug adherence is a critical factor for achieving molecular response in patients with CML. In fact, our results showed a strong inverse correlation between clinical outcome [international scale (IS)] and adherence (MMAS), with a stronger tendency in the nilotinib group than in the imatinib group. In conclusion, low occurrence of ADEs induced a high level of QoL and a good clinical response with second-generation TKI nilotinib treatment.

scholarly journals Accumulation of DNA Damage and Alteration of the DNA Damage Response in Chronic Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5364-5364
Author(s):  
Henning D. Popp ◽  
Vanessa Kohl ◽  
Johanna Flach ◽  
Susanne Brendel ◽  
Helga Kleiner ◽  
...  
Keyword(s):  
Dna Damage ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Chronic Phase ◽  
Molecular Response ◽  
Healthy Individuals ◽  
Blastic Transformation ◽  
Γh2ax Foci ◽  
Tki Treatment

The accumulation of DNA damage and the alteration of the DNA damage response (DDR) are critical features of genetic instability that is presumed to be implicated in BCR/ABL1-mediated blastic transformation of chronic myeloid leukemia (CML). The aim of our study was to analyze underlying mechanisms of genetic instability with regard to DNA damage such as DNA double-strand breaks (DSB), DSB repair and DDR signaling during blastic transformation of CML. Immunofluorescence microscopy of γH2AX was performed for quantification of DSB in peripheral blood mononuclear cells (PBMC) of 8 healthy individuals, 24 chronic phase (CP)-CML patients under current/discontinued tyrosine kinase inhibitor (TKI) treatment (21 patients in deep molecular response (DMR), 3 patients in major molecular response (MMR)), 5 CP-CML patients under current/discontinued TKI treatment with loss of MMR, 3 de novo non-treated CP-CML patients and 2 blast phase (BP)-CML patients. In addition, immunofluorescence microscopy of γH2AX/53BP1 was used for semi-quantification of error-prone DSB repair. Furthermore, immunoblotting of p-ATM, p-ATR, p-CHK1, p-CHK2 and p-TP53 was performed in PBMC of CML patients in comparison to PBMC of healthy individuals. Our analysis revealed an increase in numbers of γH2AX foci in PBMC of CP-CML patients under current/discontinued TKI treatment with loss of MMR (1.8 γH2AX foci per PBMC ± 0.4), in PBMC of de novo non-treated CP-CML patients (2.3 γH2AX foci per PBMC ± 0.7) and in PBMC of BP-CML patients (4.9 γH2AX foci per PBMC ± 0.9) as compared to the number of γH2AX foci in PBMC of healthy individuals (1.0 γH2AX foci per PBMC ± 0.1) and in PBMC of CP-CML patients under current/discontinued TKI treatment in DMR/MMR (1.0 γH2AX foci per PBMC ± 0.1) (Figure 1A and B). Analysis of co-localizing γH2AX/53BP1 foci in PBMC suggested progressive activation of error-prone nonhomologous end-joining repair mechanisms during blastic transformation in CML. Signatures of p-ATM, p-ATR, p-CHK1, p-CHK2 and p-TP53 indicated alterations of the DDR. In summary, our data provide evidence for an accumulation of DNA damage in PBMC of CML patients towards BP-CML patients. We hypothesize that ongoing DSB generation, error-prone DSB repair and DDR alterations might be critical mechanisms of blastic transformation in CML. Figure 1 Analysis of γH2AX foci in freshly isolated peripheral blood mononuclear cells (PBMC) of healthy individuals and chronic myeloid leukemia (CML) patients. (A) Exemplary immunofluorescence microscopic images of γH2AX foci (green, Alexa 488) and cell nuclei (blue, DAPI) in PBMC of a healthy individual (HEALTHY#3), a chronic phase CML patient with a deep molecular response to tyrosine kinase inhibitor (CP-CML DMR#16), a de novo non-treated chronic phase CML patient (CP-CML#1) and a blast phase CML patient (BP-CML#2). (B) γH2AX foci levels in PBMC of healthy individuals and in PBMC of CML patients. Figure 1 Disclosures Saussele: Pfizer: Honoraria; Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Fabarius:Novartis: Research Funding.

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