Prediction for Sustained Deep Molecular Response of BCR-ABL Levels in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1224-1224
Author(s):  
Koji Sasaki ◽  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Farhad Ravandi ◽  
Marina Konopleva ◽  
...  
Keyword(s):  
Research Funding ◽  
Chronic Phase ◽  
High Dose ◽  
Molecular Response ◽  
Regression Equations ◽  
Transcript Levels ◽  
Deep Molecular Response ◽  
Best Fit ◽  
Time Point

Abstract Introduction Initial treatment with tyrosine kinase inhibitors (TKI) induces excellent response in the majority of patients with CML-CP. Current guidelines recommend periodic monitoring of BCR-ABL1 levels to monitor response. During the course of treatment, recognizing early predictors of deeper response and longer-term outcomes can help guide treatment. This is relevant not only at the specified fixed time point typically reported (i.e., 3, 6, 12 months) but at any other time point when an assessment is made. Achievement of sustained deep molecular response is a goal of increasing relevance as it opens the possibility of treatment discontinuation. The objective of this study is suggest optimal BCR-ABL transcript levels at any given time, and to suggest a prediction model for sustained molecular response 4.5 (MR4.5) (BCR-ABL ≤0.0032%) for at least 2 years according to BCR-ABL levels achieved within the first 12 months of TKI therapy. Methods Response data for 630 patients with newly diagnosed CML-CP in consecutive prospective clinical trials of frontline imatinib (n=73; NCT00048672), high-dose imatinib (n=208; NCT00038469 and NCT00050531), nilotinib (n=148; NCT00129740), dasatinib (n=150; NCT00254423), and ponatinib (n=51; NCT01570868) were analyzed. Real-time PCR analysis was performed at approximately 3 month intervals during the first year and 6 month intervals thereafter. The "best fit average" molecular response was defined by robust linear regression models, with which the estimated molecular level in patients with complete cytogenetic response (CCyR) within 1 year, major molecular response (MMR) within 1 year, and sustained MR4.5 at any point were defined. The acceptable molecular response was defined by quantile regression for the 95th percentile, with which the worst 5% BCR-ABL levels in patients with CCyR within 1 year, MMR within 1 year, and sustained MR4.5 at any point were identified. Results In 630 patients, 2512 data points of BCR-ABL levels within 1 year of TKI were identified. The median follow-up for the entire cohort was 106 months (range, 0.3-177.8). The regression equations for best fit average PCR for CCyR within 1 year was Log10(PCR) = -0.2159 x (Months) + 0.1957; for MMR within 1 year, Log10(PCR) = -0.2304 x (Months) + 0.1046; for sustained MR4.5 at any point, Log10(PCR) = -0.2154 x Months -0.1161. The regression equations for acceptable PCR for CCyR within 1 year was Log10(PCR) = -0.15796 x (Months) + 1.54839; for MMR within 1 year, Log10(PCR) = -0.20999 x (Months) + 1.54839; for sustained MR4.5, Log10(PCR) = -0.22476 x (Months) + 1.50516 (Figure 1). The best fit average PCR (i.e., estimated levels achieved by the average responder in each category) for CCyR within 1 year was 0.353%, 0.079%, 0.017%, and 0.004% at 3, 6, 9, and 12 months, respectively; for MMR within 1 year was 0.259%, 0.053%, 0.011%, and 0.002% at 3, 6, 9, and 12 months, respectively; for sustained MR4.5 at any point was 0.295%, 0.067%, 0.015%, and 0.003% at 3, 6, 9, and 12 months, respectively (Table 1). To achieve CCyR within 1 year, the acceptable PCR (i.e., levels achieved by 95% of all those who eventually reach the said endpoint) response was 11.872%, 3.987%, 1.339%, and 0.450% at 3, 6, 9, and 12 months, respectively; to achieve MMR within 1 year, 8.287%, 1.943%, 0.455%, and 0.107% at 3, 6, 9, and 12 months, respectively; to achieve sustained MR4.5 at any time, 6.774%, 1.434%, 0.304%, and 0.064% at 3, 6, 9, and 12 months, respectively. Of 289 patients who eventually achieved sustained MR4.5, 288 (99%) achieved CCyR within 1 year; 268 (93%), MMR within 1 year; 201 (70%), MR4 within 1 year; 162 (56%), MR4.5 within 1 year; 72 (25%), CMR within 1 year. Of 359 patients who achieved MMR within 1 year with a minimum follow-up of 48 months, 256 (71%) achieved sustained MR4.5; of 180 patients who achieved MR4.5 within 1 year, 151 (84%); of 72 patients who achieved CMR within 1 year, 65 (90%). Conclusion Proper interpretation of early transcript levels at any time during the course of therapy may help predict later response and outcome. Such models can be built to guide therapy for patients in a continuous basis. To achieve sustained MR4.5 for at least 2 years, deeper responses are required at each time point. Our model proposes optimal values that predict the highest probability of reaching such goal. At a minimum, CCyR within 1 year is required to achieve sustained MR4.5. Disclosures Kantarjian: Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Konopleva:AbbVie: Research Funding; Genentech: Research Funding. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Daver:Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding; BMS: Research Funding; Kiromic: Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

Impact of Treatment with Frontline Nilotinib (NIL) vs Imatinib (IM) on Sustained Deep Molecular Response (MR) in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2781-2781 ◽  
Author(s):  
Andreas Hochhaus ◽  
Giuseppe Saglio ◽  
Timothy P. Hughes ◽  
Richard A. Larson ◽  
Lilia Taningco ◽  
...  
Keyword(s):  
Treatment Duration ◽  
Research Funding ◽  
Quantitative Polymerase Chain Reaction ◽  
Chronic Phase ◽  
Molecular Response ◽  
Event Analysis ◽  
Newly Diagnosed ◽  
Consolidation Phase ◽  
Time Point

Abstract Background: For pts with CML-CP treated with frontline IM, achievement of a sustained deep MR is one of the major criteria associated with successful treatment-free remission (TFR); other factors, including long duration of IM therapy and favorable Sokal risk score, have also been shown to be important. Factors affecting successful TFR in pts treated with frontline NIL are under investigation. Ongoing studies are evaluating TFR in pts who have received different durations of TKI treatment and achieved different durations of sustained MR4 (BCR-ABL1 ≤ 0.01% on the International Scale [BCR-ABL1IS ]) or MR4.5 (BCR-ABL1IS ≤ 0.0032%). Here, 6-y data from the ENESTnd trial of frontline NIL vs IM were analyzed to evaluate rates of MR4 and MR4.5 with each agent and estimate pts' rates of sustained response for ≥ 1 y while on NIL or IM treatment. Methods: ENESTnd (NCT00471497) is an ongoing, randomized trial of NIL 300 mg twice daily (BID; n = 282) or NIL 400 mg BID (n = 281) vs IM 400 mg once daily (QD; n = 283) in pts with newly diagnosed CML-CP. Data from ENESTnd based on a minimum follow-up of 6 y for pts remaining on treatment were analyzed. Rates of deep MR were reported as cumulative incidence, with pts who achieved a response at or before each time point considered responders by that time point. Rates of sustained MR4 and MR4.5 on treatment among pts who achieved each response were estimated in each arm using a time-to-event analysis. In an exploratory analysis, the MR and treatment duration criteria for entering and attempting TFR in the ENESTfreedom trial (NCT01784068; a single-arm trial of pts with CML-CP who received ≥ 2 y of frontline NIL and achieved MR4.5 prior to enrollment) were applied a posteriori to determine the proportion of pts in each NIL arm of ENESTnd who were potential candidates for TFR, per the ENESTfreedom design (in the ENESTfreedom treatment consolidation phase, pts must maintain deep MR for 1 y [with real-time quantitative polymerase chain reaction assessments every 12 weeks, and with no assessment above MR4, ≤ 2 assessments between MR4 and MR4.5, and MR4.5 in the last assessment] on NIL 300 mg BID prior to attempting TFR). Results: With a minimum follow-up of 6 y in ENESTnd, 151 (53.5%), 155 (55.2%), and 127 (44.9%) pts in the NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively, remained on study treatment; median time on treatment was 5.8, 5.9, and 5.3 y, respectively. Cumulative rates of MR4 and MR4.5 by 6 y were higher with NIL vs IM; more pts achieved MR4.5 with NIL vs IM in all Sokal risk groups (Table). Among evaluable pts at 3 mo, more achieved BCR-ABL1IS ≤ 10% at 3 mo with NIL vs IM (NIL 300 mg BID, 234/258 [90.7%]; NIL 400 mg BID, 232/260 [89.2%]; IM, 176/264 [66.7%]); within each arm, rates of MR4.5 by 6 y were higher among pts who achieved BCR-ABL1IS ≤ 10% at 3 mo vs those with BCR-ABL1IS > 10% at 3 mo. Estimated rates of sustained MR4 and MR4.5 for ≥ 1, ≥ 2, and ≥ 3 y in pts achieving each response were high in all 3 arms; estimated rates of sustained MR4.5 for ≥ 1 y were 81.5%, 84.3%, and 84.4% in the NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively. By the data cutoff, 54.3% (153/282) and 54.8% (154/281) of pts in the NIL 300 mg BID and NIL 400 mg BID arms, respectively, had received ≥ 2 y of NIL treatment and achieved MR4.5 (the treatment duration and MR criteria for entering the ENESTfreedom treatment consolidation phase). In the 2 NIL arms, 37.9% (107/282) and 34.2% (96/281) of pts, respectively, had received ≥ 3 y of NIL treatment with sustained MRD for ≥ 1 y (the criteria for attempting TFR in ENESTfreedom). Conclusion: In ENESTnd, NIL resulted in higher rates of MR4 and MR4.5 than IM. Once achieved, these deep MRs were durable in all 3 treatment arms, with > 80% of pts who achieved MR4.5 maintaining this response for ≥ 1 y. The higher rates of deep MR achieved with frontline NIL vs IM may enable more pts to qualify to attempt experimental TFR in a clinical trial. After a minimum follow-up of 6 y, 37.9% of pts (107/282) treated with NIL 300 mg BID in ENESTnd had the treatment duration and sustained deep MR equivalent to those required for attempting TFR in ENESTfreedom. Disclosures Hochhaus: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Saglio:Novartis: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Hughes:Bristol-Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Larson:Bristol-Myers Squibb: Consultancy; Ariad: Consultancy, Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Research Funding. Taningco:Novartis Pharmaceuticals: Employment. Deng:Novartis Pharmaceuticals: Employment. Menssen:Novartis Pharma Basel Switzerland: Employment.

High-Dose (HD) Imatinib Provides Better Responses in Patients with Untreated Early Chronic Phase (CP) CML.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2143-2143 ◽  
Author(s):  
tsuko Aoki ◽  
Hagop Kantarjian ◽  
Susan O’Brien ◽  
Moshe Talpaz ◽  
Francis Giles ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Standard Dose ◽  
Chronic Phase ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Grade 3 ◽  
Sequential Trials ◽  
Time Point

Abstract Imatinib (standard dose, SD, 400mg/day) is highly effective in patients with CML in early chronic phase (CP). However, in a phase I study there was clear dose-response correlation and no maximum tolerated dose was identified up to 1000mg/day. Early reports suggested higher response rates with high dose (HD) imatinib (800 mg/day) in this setting. Here we report the long-term follow-up results of high-dose imatinib for patients with CML in early CP. Patients were included from 3 sequential trials: the first included 50 patients all treated with 400mg daily, and 2 subsequent studies included 208 patients all treated at 800 mg daily as the starting dose. There were no differences in pre-treatment characteristics between HD group and SD groups. The median age was 48 years in both groups. Median follow-up was 58 months for SD and 34 months for HD group. Patients treated with HD had a higher rate of complete cytogenetic responses (91% vs 76% in SD group, p=0.002) and these occurred earlier, with 88% achieving a complete cytogenetic response (CGCR) after 6 months of therapy (vs 56% with SD; p<0.00001). The cumulative incidence of major molecular response (MMR) was significantly higher in HD group at 6, 12, 36 and 48 month of follow-up: in HD group, 33%, 58%, 82% and 88% of patients had achieved this response at each time point (vs 2%, 22%, 64% and 67% in the SD group; p<0.00001, <0.00001, 0.01 and 0.002 at respective time point). The cumulative incidence of complete molecular response (CMR) was also significantly higher in HD group at 6, 12, 36 and 48 month of follow-up: in HD group, 8%, 20%, 53% and 66% of patients had achieved this response at each time point (vs 0%, 4%, 27%, and 34% in the SD group; p=0.05, 0.007, 0.003 and 0.0006 at respective time point). Progression-free and transformation-free survivals were significantly better in HD group (p=0.02 and 0.005). Overall survival was excellent in both groups with no difference between them. Grade 3 or 4 hematologic toxicity was more frequent in HD group whereas extramedullary toxicity was similar in both groups. The frequency of ≥ grade 3 anemia, neutropenia and thrombocytopenia in HD group was 12, 35, 29%, respectively while those in SD group were 4, 20, and 12%, respectively. The median actual dose in HD group was 800 mg at 24 months, with only 20% (15/75) of patients taking 400 mg or less at 36 months. We conclude that high-dose imatinib therapy in early CP-CML is associated with higher rates of CGCR, MMR and CMR, and these occur earlier, translating into better progression-free and transformation-free survival. Although HD imatinib is overall well tolerated, there is a higher rate of myelosuppression, most frequently occurring during the first weeks of therapy.

scholarly journals Personalized Daily Doses of Imatinib By Therapeutic Drug Monitoring Increase the Rates of Molecular Responses in Patients with Chronic Myeloid Leukemia. Final Results of the Randomized OPTIM Imatinib Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 133-133 ◽  
Author(s):  
Philippe Rousselot ◽  
Hyacinthe Johnson-Ansah ◽  
Françoise Huguet ◽  
Laurence Legros ◽  
Martine Escoffre-Barbe ◽  
...  
Keyword(s):  
Research Funding ◽  
Dose Adjustment ◽  
Chronic Phase ◽  
Similar Proportion ◽  
Therapeutic Drug ◽  
High Dose ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Daily Dose

Abstract Background Imatinib mesylate (IM) at 400 mg/d remains a standard for first line therapy in patients (pts) with newly diagnosed chronic phase CML (CP-CML). A sub analysis of the IRIS study (Larson et al. Blood, 2008) demonstrated that pts with high IM trough levels achieved higher rates of major molecular response (MMR). The level of 1000 ng/ml was established as the [C]min value threshold to predict molecular response (Picard et al. Blood, 2007). We conducted a randomized trial to evaluate the value of IM dose optimization based on the monitoring of [C]min levels in newly diagnosed CP-CML pts (OPTIM-imatinib trial, EudraCT number 2008-006854-17). Patients and Methods Pts diagnosed with CP- CML for less than 3 months, not previously treated or treated with IM for less than 3 months were eligible and treated with IM 400 mg/d. IM [C]min was determined by chromatography-tandem mass-mass spectrometry 15 days after enrollment. Pts with a [C]min < 1000 ng/ml were randomized between a dose-increase strategy aiming to reach the threshold of 1000 ng/ml (arm A1) versus standard IM management (arm A2). Pts with [C]min levels ≥1000 ng/ml were observed (arm A3). All pts were managed according to the ELN 2009 recommendations (amended with ELN 2013 recommendations). IM [C]min levels were assessed monthly in A1 and A2 and every 3 months in A3. BCR-ABLIS was assessed every 3 months. The primary end-point was MMR rates at 12 months. Results One hundred thirty nine pts were enrolled. Median follow-up was 31 months. Median age was 64y (25 to 88y), sex ratio (M/F) was 1.4 and Sokal score distribution was 21%, 41% and 38% for high, intermediate and low categories respectively, equally distributed in the 3 arms. In 6 pts the initial [C]min was not assessed (3 were intolerant and 3 declined the dosage). Thus 133 pts were studied. In 86 pts (65%), initial [C]min value was < 1000 ng/ml. These pts were randomized between A1 (43 pts) and A2 (43 pts). [C]min was ≥1000 ng/ml in the 47 remaining pts followed in A3. Table 1 shows the significant improvement of the median IM [C]min after dose adjustment in A1 (p<0.0001) as compared to standard management in A2. Correspondingly, IM daily dose increased in A1 (p<0.0001) to reach a mean value of 600 mg/d. In the experimental A1 arm, the distribution of IM doses at 12 months was 13% for 500 mg/d, 30% for 600 mg/d, 34% for 800 mg/d whereas 16% of the pts remained at 400 mg/d and 7% were dose decreased at 300 mg/d. During follow-up, a similar proportion of pts with AE was observed in A1 (58%) and A2 (51%). Eight SAE related to IM were equally distributed in A1, A2 and A3. Cumulative incidences of treatment discontinuation were comparable in the 3 arms (overall, 18.8% by 12 months and 34.1% by 24 months). Reasons for discontinuation were not similar in A1 and A2 with a trend for more treatment failures in A2 as compared to A1 (60% versus 18%, p=0.08). At 12 months, MMR was achieved in 27 out of 43 pts (63%; 95%CI 49-77) in A1 as compared to 16 out 43 pts (37%; 95%CI 23-51) in A2 (p=0,031). The rates of MMR were not statistically different between A1 and A3 (p=0.12). Conclusions Only 1/3 of pts on IM400 were correctly dosed and may not require systematic high dose IM. Two-thirds of the pts were not exposed enough to IM at standard dose and may benefit from individualized strategies. A tailored dose adjustment based on pharmacology resulted in higher MMR rate at 12 months (63% vs 37%), a magnitude in line with the results previously reported with second generation tyrosine kinase inhibitors or high dose IM front line. Our results may provide a strong rational to early personalize the use of IM and IM generic formulations in order to optimize the outcome for each patient. This study was supported by a grant from the French Department of Health (Programme Hospitalier de Recherche Clinique). Table 1. Median [C]min (ng/ml; (95% CI)) Initial Assessment M3 M6 M9 M12 A1 591; (508-654) 838; (746-922) 1001; (748-1261) 1062; (918-1221) 1013; (830-1277) A2 651; (558-797) 605; (487-786) 591; (517-722) 605; (460-720) 646; (576-894) A3 1314; (1199-1514) 1032; (899-1143) 1002; (784-1205) 935; (737-1073) 1000; (846-1098) Mean IM daily dose (mg/d; (95% CI)) Inclusion M3 M6 M9 M12 A1 400 538; (508-568) 611; (563-658) 607; (545-668) 600; (535-665) A2 400 395; (387-402) 392; (383-401) 391; (381-401) 391; (381-401) A3 400 400; (400-400) 398; (385-410) 389; (376-402) 382; (370-395) Disclosures Rousselot: BMS: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Consultancy. Johnson-Ansah:BMS: Speakers Bureau; Hybrigenics SA: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau. Huguet:PFIZER: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding. Legros:Novartis: Research Funding, Speakers Bureau; ARIAD: Speakers Bureau; BMS: Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Coiteux:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau. Deau:BMS: Honoraria. Mahon:ARIAD: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Delayed Achievement of Molecular Responses Is Associated with Increased Risk of Progression among Patients (pts) with Chronic Myelogenous Leukemia (CML) In Chronic Phase (CP) Treated with Imatinib (IM).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 432-432 ◽  
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop M. Kantarjian ◽  
Dan Jones ◽  
Guillermo Garcia-Manero ◽  
Susan O’Brien ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
White Cell Count ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
P Value ◽  
High Dose ◽  
Molecular Response ◽  
Transcript Levels ◽  
Increased Risk ◽  
Risk Of Progression

Abstract Background: Achieving a cytogenetic (CG) response or a molecular response after imatinib therapy has been associated with improved event-free (EFS) and transformation-free survival (TFS). It is unclear whether achieving these responses earlier confers an advantage. A recent update of the IRIS trial suggests that achieving a major CG response (MCyR) at 12, 18 or 24 months (mo) confers a similar TFS advantage. Another report (J Clin Oncol2006;24:454) suggests that achieving a complete CG response (CCyR) at 12 or 24 mo confers equal prognosis to patients. Although some patients may indeed improve their response with continued therapy, a pt not in CCyR faces the competing possibilities of eventually achieving a CCyR vs progressing. Methods: We analyzed the risks of improving the CG response vs progressing for pts not in CCyR at different times to determine whether early responses confer an advantage. 258 pts with CML CP treated with IM were analyzed. Progression was defined as transformation to AP or BP, loss of CHR or major CG response, or a doubling of the white cell count to more than 20x109/L. Results: After 3 mo of IM therapy, 77 (74%) of 104 assessable pts for CG response had a CCyR whereas 17 (16%) progressed. These differences were consistently significant at 6 and 12 mo (p=0.04) (Table 1). We then analyzed the long term risk of progression vs the probability of achieving CCyR according to the molecular response at different time points (Table 2). Patients with Bcr-Abl/Abl transcript levels &gt;1–10 after 3 mo of therapy had a 92% probability of achieving CCyR with continued therapy, similar to the 98% for those with ≤1. However, they have a significantly higher risk of eventual progression that is more similar to that of pts with values of &gt;10. The risk of progression increases to 23% if transcript levels &gt;10 at 6 mo. Conclusion: These results suggest that while the risk of progression may be similar for pts who achieve a CCyR regardless of the time at which that is attained, those who fail to obtain a CCyR within the first 12 mo of IM therapy have higher rates of disease progression. This risk is discernible as early as 3 mo into IM therapy and may provide a rationale for therapies that induce higher rates of early molecular response (e.g. high-dose imatinib, new tyrosine kinase inhibitors). Table 1 Time on imatinib No. not in CCyR No. with eventual outcome with continued therapy (%) CCyR Progression p value 3 months 104 77 (74) 17 (16) 6 months 47 28 (60) 12 (26) 0.04 12 months 26 16 (62) 8 (31) Table 2 % Probability Months %Bcr-Abl/Abl No. CCyR Progression p value ≤ 1 87 98 2 3 &gt; 1–10 76 92 11 0.04 &gt; 10 30 67 13 ≤ 1 140 99 4 6 &gt; 1–10 34 91 9 0.005 &gt; 10 13 62 23

Increasing Frequency and Marked Stability of Complete Molecular Response Is Observed in Imatinib-Treated CML Patients with Long-Term Follow Up.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 430-430 ◽  
Author(s):  
Susan Branford ◽  
John Francis Seymour ◽  
Andrew Grigg ◽  
Chris Arthur ◽  
Kevin Lynch ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Leukemic Cells ◽  
Molecular Response ◽  
Second Line ◽  
First Line ◽  
Important Indicator ◽  
Complete Molecular Response ◽  
Time Point ◽  
Marked Stability

Abstract The degree of reduction of BCR-ABL in imatinib-treated patients with chronic phase CML is an important indicator of prognosis. The IRIS trial established that with first-line therapy patients with a major molecular response (MMR, 3 log reduction from a standardized baseline value for untreated patients) have a significantly more favorable progression free survival. Although 40% achieved a MMR by 12 months, very few had undetectable BCR-ABL according to strict PCR sensitivity criteria. We measured peripheral blood BCR-ABL levels by quantitative PCR at 3 to 6 month intervals in 155 patients with chronic phase CML enrolled in clinical trials of imatinib for up to 6 years. We aimed to (i) determine if BCR-ABL levels continued to decline over time, and (ii) evaluate the stability and significance of undetectable BCR-ABL. The patients included the Australasian subset of IRIS trial patients treated with 400mg of imatinib; 29 first-line patients evaluated for a median of 69 months (25th to 75th percentile range (pr) 58–72) and 24 second-line patients for a median of 54 months of imatinib (pr 38–60). 102 de-novo patients enrolled in the TIDEL trial of 600mg imatinib were evaluated for a median of 39 months (pr 30–42). Complete molecular response (CMR) was defined as undetectable BCR-ABL at a PCR sensitivity of at least 4.5 logs below the standardized baseline value confirmed on subsequent analysis after at least 3 months. The BCR control transcript level determined sensitivity and was dependent on RNA quality and reverse transcription efficiency. Of note CMR may not indicate eradication of leukemic cells, rather a reduction of BCR-ABL below the detection limit. CMR occurred in 34 patients who had 178 analyses after achieving CMR (median 4 tests per patient) and a median follow up of 15 months (pr 9–24). Very low level BCR-ABL was detected in 3 patients, the remaining 31 had undetectable BCR-ABL on every subsequent assay. Of the IRIS trial patients treated with first-line imatinib, 41% achieved a CMR by 69 months, a frequency significantly higher than occurred in these patients at 24 months (7%, p=0.006). The rate of CMR appeared to increase substantially beyond the 3 year time point (7%, 24% and 34% at 3, 4 and 5 years). 75 patients achieved MMR but not CMR and were followed for a median of 24 months after achieving MMR (pr 17–33). Six of 75 patients (8%) lost MMR as defined by &gt;2-fold rise in BCR-ABL and loss of MMR on 2 consecutive analyses. The median fold rise was 18-fold (4 to 1900-fold), of whom 1 went on to blast crisis. Four of the 6 patients had BCR-ABL mutations detected at the time of the rise and 1 of the remaining patients had duplicate Ph. MMR was lost in these 6 patients within 18 months of its achievement. The overall rate of CMR and MMR (including patients with CMR) did not differ significantly between the 3 treatment groups at the 3 year time point (CMR 7%, 8% and 18%; MMR 66%, 71% and 70% for first-line 400mg, second-line 400mg and first-line 600mg respectively). In conclusion at a median follow-up of 5.75 years of 400mg first-line imatinib, CMR was achieved in 41% of patients. Importantly, of all patients who achieved a CMR in this study using strict criteria to define the sensitivity of analysis, none have lost MMR and 91% have maintained CMR. The slow acquistion and marked stability of CMR favour the notion that the leukemic stem cell pool is steadily declining with prolonged exposure to imatinib.

Dasatinib Is Well-Tolerated and Efficacious in Imatinib-Intolerant Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1128-1128 ◽  
Author(s):  
Hanna Jean Khoury ◽  
Michael J. Mauro ◽  
Yousif Matloub ◽  
Tai-Tsang Chen ◽  
Erkut Bahceci ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Median Duration ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Molecular Response

Abstract Abstract 1128 Poster Board I-150 Imatinib (IM), a tyrosine kinase inhibitor (TKI), has been the mainstay of treatment for chronic phase chronic myeloid leukemia (CP-CML). However, IM resistance and intolerance are of considerable clinical relevance. Dasatinib (DAS), a second-line TKI, is effective in the IM-intolerant patient population. The purpose of this study was to determine baseline factors that can affect DAS response and evaluate long term efficacy in this population. Intolerance to IM was defined as ≥ Grade 3 non-hematologic toxicity and/or Grade 4 hematologic toxicity lasting > 7 days. A total of 271 Ph+ CP-CML IM-intolerant patients who received DAS were pooled from two randomized trials (Phase II-trial, CA 180013 and Phase III trial, CA 180034). DAS doses were 50 mg BID (n=43), 70 mg BID (n=141), 100 mg QD (n=43) or 140 mg QD (n=44). At baseline, the median duration of disease for the IM-intolerant patients was 24 months (range: 0.9-182.5) and the median duration of IM therapy was 9 months (range: 0.03-69.06). Of these patients, 46 (17%) had hematologic toxicity and 228 (84.1%) had non-hematologic toxicity to IM. Seventy-nine (29%) patients had prior complete cytogenetic response (CCyR) on IM and 171 (63%) patients did not. The data for prior CyR to IM was not reported for 21 (7.7%) patients. Of the 79 patients who had achieved CCyR on IM, 30 patients had maintained CCyR and 49 patients had lost this response prior to start of DAS. Of the 171 patients who did not achieve CCyR on IM, 62 (36.3%) had been on IM for 3 12 months and 109 (63.7%) for < 12 months. At 2-year follow up of the 271 patients treated with DAS, 121 (44.6%) discontinued DAS (7.4% due to hematologic toxicity and 14% due to non-hematologic toxicity). Of the patients who were intolerant of IM due to hematologic toxicity (n=46), 10 (21.7%) discontinued DAS due to hematologic toxicity, and 3 (6.5%) due to other toxicities. Of the patients with non-hematologic IM-intolerance (n=228), 10 (4.4%) discontinued DAS due to hematologic toxicity, and 35 (15.4%) due to other toxicities. The median average daily dose of DAS was 99 mg/day in the population who achieved CCyR on DAS and 71.5 mg/day in the population who did not achieve CCyR on DAS. The probability of achieving CCyR on DAS was 43.5% in patients with hematologic IM-intolerance versus 78.9% with non-hematologic IM-intolerance. The CCyR, major molecular response (MMR), progression-free survival (PFS) and overall survival (OS) at 2-year follow up for the groups classified by their CCyR status at start of DAS or IM-intolerance status are summarized in Table 1. Conclusions DAS was well-tolerated and associated with high rates of CyR in IM-intolerant patients. Patients with a prior CCyR to IM and those who switched due to non-hematologic imatinib-intolerance had the highest rates of CCyR and MMR on DAS, while patients without CCyR after more than 12 months of IM therapy or IM-intolerance due to hematologic toxicity had the lowest rates of CCyR and MMR. Disclosures Khoury: BMS: Honoraria; Wyeth: Honoraria; Novartis Pharmaceuticals: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. Mauro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Matloub:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Bahceci:Bristol-Myers Squibb: Employment. Deininger:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding.

Occurrence, Management, and Outcomes In Patients with Pleural Effusion During Dasatinib Treatment for Chronic-Phase Chronic Myeloid Leukemia (CML-CP) In the First-Line Setting: Analysis of the DASISION Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2282-2282 ◽  
Author(s):  
Kimmo Porkka ◽  
Michele Baccarani ◽  
Andreas Hochhaus ◽  
Hagop Kantarjian ◽  
Satu Mustjoki ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Research Funding ◽  
Chronic Phase ◽  
Risk Scores ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Once Daily ◽  
Management Interventions ◽  
Grade 3

Abstract Abstract 2282 Background: The Phase 3 DASISION trial comparing dasatinib 100 mg once daily with imatinib 400 mg once daily as initial treatment in patients (pts) with newly diagnosed CML-CP has demonstrated superior efficacy and favorable safety of dasatinib after a minimum of 12 months of follow-up (Kantarjian, H, et al. N Engl J Med 2010;362:2260). While fluid retention was more frequent with imatinib than with dasatinib, pleural effusion was seen only with dasatinib. Here, we provide a detailed analysis of pts experiencing pleural effusion, a clinically relevant adverse drug reaction. Methods: 519 pts with newly diagnosed, treatment-naive CML-CP (median disease duration of 1 month) were randomly assigned to either dasatinib 100 mg once daily (259 pts) or imatinib 400 mg one daily (260 pts). Key endpoints included complete cytogenetic response (CCyR), major molecular response (MMR) and safety. All pts were assessed by chest x-ray at baseline and at 6 months after randomization, or more frequently, if indicated clinically. Pts with pleural effusion at baseline were excluded. Pleural effusion was graded according to CTCAE version 3 (grade 1, asymptomatic; grade 2, symptomatic, up to 2 therapeutic thoracenteses; grade 3, symptomatic requiring supplemental oxygen, < 2 therapeutic thoracenteses; grade 4, life-threatening, hemodynamic instability). Results: After a minimum follow-up of 12 months with median treatment duration of 14.3 months (range, 0.3–25.8), 26 (10%, median age, 60 years) of the 258 dasatinib-treated pts (median age, 46 years) experienced pleural effusion. Of the pts with pleural effusion, 6 (23%) had low, 17 (65%) had intermediate and 3 (12%) had high Hasford risk scores. There were no grade 3 or 4 pleural effusion events. All events were grade 1(2%) or grade 2 (8%). Most events (n = 22, 85%) occurred more than 8 weeks after the start of study drug. In pts who had a pleural effusion, the median time to the event was 28 weeks (range, 4–88). Lymphocytosis (defined as peripheral blood lymphocyte count > 3.6 × 109/L) was noted in 11 (42%) of the 26 pts with pleural effusion, as compared to 46 (20%) of 232 pts with no pleural effusion. Pleural effusion was managed by dose modification and/or medical intervention. Therapy was interrupted in 19 pts, and the dose of dasatinib was reduced in 8 pts (4 pts, to 80 mg; 1 pt, to 70 mg; 3 pts, to 50 mg). Twelve pts received diuretics, 7 received corticosteroids, and only 1 pt underwent therapeutic thoracentesis. Only 3 pts (1.2%) discontinued therapy due to pleural effusion (grade 2). Eleven pts who continued dasatinib had resolution of their pleural effusion. Five pts had recurrent effusions. Of the 26 pts with pleural effusion, 24 (92%) achieved a CCyR and 17 (65%) achieved a MMR by 12 months of treatment; the corresponding CCyR and MMR rates in the total pt population were 83% and 46%, respectively Seven of the 8 pts with pleural effusion who reduced their dose achieved CCyR and MMR. Conclusion: In pts with newly diagnosed CML-CP treated with dasatinib as initial therapy, pleural effusion was mild to moderate in severity, and was manageable with dose interruption and/reduction and/or a short course of diuretics and/or corticosteroids. The occurrence of pleural effusion and management interventions did not negatively affect the achievement of CCyR or MMR. These findings are in line with data reported previously for second-line dasatinib in CML pts resistant or intolerant to imatinib (Porkka, K, et al. Cancer 2010;116:377). Furthermore, pleural effusion and peripheral lymphocytosis may be indicative of immune-mediated antitumor activity of dasatinib. Disclosures: Porkka: BMS, Novartis: Consultancy, Honoraria, Research Funding. Baccarani: Novartis, Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Brostol-Myers Squibb, Novartis: Consultancy, Research Funding. Kantarjian: BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Mustjoki: BMS, Novartis: Honoraria. Bradley-Garelik: Bristol-Myers Squibb: Employment, Equity Ownership. Zhu: Bristol-Myers Squibb: Employment. Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria.

Seven-Year Follow-up Data on Sequential Prospective Trials of Imatinib 400mg Vs 800mg Daily Schedule for Front-Line Treatment of Chronic Myeloid Leukemia (CML).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3438-3438
Author(s):  
Naveen Pemmaraju ◽  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Srdan Verstovsek ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Chronic Phase ◽  
Annual Rate ◽  
Molecular Response ◽  
Free Survival ◽  
Cumulative Rate ◽  
Prospective Trials

Abstract Abstract 3438 Background: The standard of care for most patients (pts) with CML has been imatinib mesylate at a dose of 400mg by mouth daily. Earlier studies have suggested that there may be a benefit to pts to start treatment at a higher dose as this may result in faster and more durable responses to imatinib. It is not yet known whether long-term event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) will be impacted by the higher dosing schedule. Objectives: To determine the long term responses and clinical benefit of imatinib 800mg daily versus 400mg daily dosing when used as upfront treatment strategy in CML. Methods: We conducted sequential prospective trials using imatinib 400mg or 800mg daily as initial therapy for patients with previously untreated chronic phase CML. Results: A total of 281 pts were included in these trials: 208 treated with 800mg and 73 with 400mg. The median follow-up for each group was 79 months (range: 3–107) and 110 months (range: 2–116). The overall, cumulative rate of complete cytogenetic response (CCyR) was 91% and 87%, respectively (p=0.49) for those treated with high- and standard-dose, and the cumulative rate of major molecular response (MMR) was 87% and 78%, respectively (p=0.06). Rates of CCyR at 12 months were 90% and 66%, respectively (p < 0.001), and MMR at 18 months 82% and 68%, respectively (p=0.04). A significantly better EFS (definition per IRIS criteria) was observed for the 800 mg group compared to that in the 400mg group (log-rank test, p=0.049; estimated 7-year EFS 86% vs 76% by Kaplan-Meier method). No significant differences were seen for survival free from transformation to accelerated and blast phase (p = 0.46) and overall survival (p = 0.27). For OS, thus far 19 pts in the 800mg group have died (2 probable CML-related, 3 unknown causes, 14 non CML related) compared to 13 pts (10 probable CML-related, 3 non CML-related) in the 400mg group. The table below shows the annual rate of events and transformation for each dose group. Treatment discontinuation for toxicity occurred in 16 (8%) pts treated with 800mg and 6 (8%) pts treated with 400mg. Conclusions: At 7-year follow up, pts treated with 800mg demonstrated a significantly better EFS (by IRIS criteria) compared to those treated with 400mg. There is a trend for a lower annual rate of events and transformation with the higher dose, particualry in the earlier years, but no difference in OS. These results suggest a modest benefit for patients treated with higher dose imatinib. Disclosures: Off Label Use: imatinib at dose of 800mg po daily for CML. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Verstovsek:Incyte Corporation: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. Cortes:Pfizer: Consultancy, Research Funding; BMS: Honoraria, Research Funding; Novarits: Honoraria, Research Funding.

EUTOS Score Is Not Predictive for Survival and Outcome in Patients (pts) with Chronic Myeloid Leukemia in Early Chronic Phase (CML-CP) Treated with Tyrosine Kinase Inhibitors (TKIs) At MD Anderson Cancer Center (MDACC),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3769-3769
Author(s):  
Aziz Nazha ◽  
Elias Jabbour ◽  
Jorge E. Cortes ◽  
Susan O'Brien ◽  
Jenny Shan ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Inhibitors ◽  
Standard Dose ◽  
Chronic Phase ◽  
Cancer Center ◽  
High Dose ◽  
Molecular Response ◽  
Phase Ii Trials ◽  
Free Survival ◽  
Eutos Score

Abstract Abstract 3769 Background: Until recently, prognosis of pts with CML treated with TKI was based on scores developed in the chemotherapy and interferon era. Hasford and colleagues [Blood. 2011;(118):686–692] have identified the EUTOS score, using the percentage of basophils and spleen size, as a significant tool to predict the probability of achieving 18-month complete cytogenetic response (CCyR) and progression-free survival in patients treated with imatinib. Aims: To validate the EUTOS score in an independent MDACC cohort of pts, with early CML-CP treated with standard-dose imatinib, high-dose imatinib, dasatinib, and nilotinib, and its ability to predict transformation-free survival (TFS), event-free survival (EFS) and overall survival (OS). Methods: 465 consecutive pts with newly diagnosed CML–CP (0 – 6 months from diagnosis to TKI treatment) were treated with imatinib 400 mg daily (n=71), imatinib 800 mg daily (n=208), and 2nd TKIs (n=186; dasatinib n=88, nilotinib n=98) in sequential phase II trials. Entry criteria were similar for all trials. EUTOS score = (7 x basophils %) + (4 x spleen cm BCM). A EUTOS score of >87 indicates high-risk and ≤87 low-risk. Results: 465 pts with CML-CP were assessed. Median age was 47 years (range, 15–85). Median time from diagnosis to TKI therapy was 1 month (range, 0 to 6). 319 (69%), 112 (24%), and 34 (7%) pts were in low, intermediate, and high-Sokal score category, respectively. Median basophils percentage at baseline was 3 (range, 0 to 19). Median splenomegaly size was 0 cm (range, 0 to 30). 118 pts (25%) received previous cytoreduction therapy. Median follow-up was 117 months (range, 16 to 130) for pts receiving standard-dose imatinib, 88 months (range, 4 to 118) for those receiving high-dose imatinib, and 30 months (range, 3 to 69) for those receiving 2nd TKI. The overall CCyR rates were 87%, 91%, and 95%, respectively. The 4-year EFS, TFS, and OS rates for the whole group were 84%, 94%, and 95%, respectively. Overall, of the 465 pts, 427 (92%) were in low EUTOS score category (Table 1). Pts with low EUTOS score had higher rates of CCyR at anytime compared to pts with high EUTOS score (93% versus 81%, p=0.02). This difference was mainly significant among pts receiving 2nd TKI (p=0.03) while it was not different among pts receiving imatinib (p=0.27). There was no difference in the rates of major molecular response (85% versus 81%, p=0.48) between pts with low and high EUTOS score. There was no difference in TFS, EFS, and OS rates between pts with low and high EUTOS score, overall and among specific therapy (Table 1). Conclusion: Eight percent of pts with CML-CP treated at MDACC are of high EUTOS score. In this population, the EUTOS score was not predictive for overall MMR, TFS, EFS, and OS. Disclosures: Cortes: BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Nilotinib Versus High-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses to Standard-Dose Imatinib: Updated Data From RE-Nice Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3775-3775 ◽  
Author(s):  
Soo-Young Choi ◽  
Sung-Eun Lee ◽  
Soo-Hyun Kim ◽  
Eun-Jung Jang ◽  
Jin-hwa Lee ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Standard Dose ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Molecular Response ◽  
Long Term Outcomes ◽  
First Line

Abstract Abstract 3775 Background. In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In contrast, several clinical studies investigating the clinical implications of suboptimal response showed that patients with suboptimal responses tend to have poor long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this prospective study, we investigated whether switching to nilotinib (NIL) or high-dose IM may be more effective for patients with suboptimal molecular response to IM as first-line therapy. Methods. Early chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months (≤ 18 to ≥24 months) on first-line IM therapy at a daily dose of 400 mg were enrolled in this clinical trial, and informed consents were obtained from all patients. In NIL arm, patients received oral dose of 400 mg BID (800 mg/day) and in high-dose IM arm, patients received 800 mg/day administrated as 400 mg BID. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative MMR, MR4.0 and undetectable molecular residual disease (UMRD) rates during further 24 month follow-up. Safety profiles will also be assessed. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment. Results. With a data cut-off date of 10 Jul 2012, a total of 43 patients were randomized into NIL arm (n = 22) or high-dose IM arm (n = 21). With a median follow-up of 15 months (range, 1–36), all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL1 transcript levels was observed in all patients. Cumulative incidence (CI) of MMR by 12 months showed no significant difference between NIL arm and high-dose IM arm (37.8 ± 11.9% vs 34.8 ± 10.6%, P = 0.789). In NIL arm, 3 in 22 (14%) and 2 in 22 (9%) patients achieved MR4.0 and UMRD, respectively, and in high-dose IM arm, 1 in 21 (5%) patients achieved MR4.0. Overall, the patients treated with high-dose IM showed toxicities more frequently, such as fatigue, dyspnea and decreased phosphate. In addition, 10 patients in high-dose IM arm have cross-over to NIL treatment due to lack of response (n=9) and intolerance (n=1), and the median duration of NIL treatment was 14 months (range, 7–26 months). Among them, 5 (50%) patients have achieved MMR with a median NIL treatment duration of 12 months (range, 3–18). Conclusions. These results demonstrate that early switching to NIL or dose escalation of IM could be recommended, considering the results of standard dose of IM in suboptimal molecular responders. When the tolerability of treatment was considered for switching to NIL or high-dose IM, NIL may be preferred. Through further clinical investigation on a large patient population and longer period observation, the efficacy and safety of early intervention of suboptimal molecular response using NIL or dose escalation of IM will be needed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: No relevant conflicts of interest to declare.

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