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.

scholarly journals EUTOS score is not predictive for survival and outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors: a single institution experience

Blood ◽  
2012 ◽  
Vol 119 (19) ◽  
pp. 4524-4526 ◽  
Author(s):  
Elias Jabbour ◽  
Jorge Cortes ◽  
Aziz Nazha ◽  
Susan O'Brien ◽  
Alfonso Quintas-Cardama ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Free Survival ◽  
Eutos Score

Abstract To validate the recently reported European Treatment and Outcomes Study (EUTOS) score, we applied it to 465 patients with early chronic phase chronic myeloid leukemia treated with standard-dose imatinib (n = 71), high-dose imatinib (n = 208), or second-generation tyrosine kinase inhibitors (n = 186), and assessed its ability to predict event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS). The median follow-up was 69 months. The overall complete cytogenetic response and major molecular response rates were 92% and 85%, respectively. The 3-year EFS, TFS, and OS rates were 86%, 95%, and 97%, respectively. Of the 465 patients, 427 (92%) were in low EUTOS score category. There was no difference in the major molecular response, TFS, EFS, and OS rates between patients with low and high EUTOS score, overall and within specific therapies. In conclusion, 8% of patients with chronic phase chronic myeloid leukemia treated at our institution are in the high EUTOS score; in this population, the EUTOS score was not predictive for outcome.

scholarly journals Phase III Randomized Study of Imatinib Therapy in Chronic Phase Chronic Myeloid Leukemia Comparing Standard Dose-Escalation with Progressive Dose-Escalation (JALSG CML207 study)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 941-941
Author(s):  
Koichi Miyamura ◽  
Shigeki Ohtake ◽  
Kazunori Ohnishi ◽  
Noriko Usui ◽  
Chiaki Nakaseko ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Research Funding ◽  
Standard Dose ◽  
Randomized Study ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Molecular Response ◽  
Group A ◽  
Group B

Abstract Imatinib mesylate (IM) given orally at a daily dose of 400 mg was the standard of care as initial therapy for patients with chronic myeloid leukemia (CML) in the chronic phase (CML-CP), before 2ndTKI era. Treatment guidelines by European Leukemia Net (ENL) propose dose escalation based on clinical assessments of disease response in 2006. Preclinical data and results of single-arm studies raised the suggestion that better results could be achieved with a higher dose. However, randomized study to compare high-dose IM (800 mg) with the standard dose (400 mg) as front-line in all CML high-risk patients did not support the extensive use of high-dose IM. To improve the results of CML therapy, another alternative strategy is a dose-escalation based on more aggressive clinical assessments of disease response in comparison with the standard ELN proposed. In 2007, we conducted a prospective randomized study to compare different dose escalation programs; the standard-dose escalation program proposed by ENL (Group A) and the aggressive dose escalation program (Group B) among newly diagnosed patients with CML-CP. The aggressive dose escalation program consisted of the following interventions. If the patients do not obtained a complete cytogenetic response at 3 months or do not reach a major molecular response (MR3, IS=0.1%), IM is increased from standard dose of 400mg daily to 600 mg daily. The primary endpoint is the rate of major molecular response at 12 months, which is a surrogate for long-term progression-free survival (PFS). It is also a surrogate for complete molecular response, which is pointed out recently to be the condition for treatment free survival. Total 248 patients entered to this study between June 16 2007 and June 15, 2011. Median age was 49 years old (range 15-69); 86 were female and 162 were male. Sokal score index was high-risk in 46 patients, intermediate-risk in 77 and low-risk in the remaining. White blood cell count at diagnosis was 43X10^9/L in median (10-881 in range). There was no significant difference between Group A (N=126) and Group B (N=127) according to these factors. Overall survival was 100%, 98% and 98% at 1, 2 and 3 years after treatment, respectively. Three patients developed blast crisis during 3 years (day 177, 272, 481) and all received hematopoietic stem cell transplantation (HSCT). Two other patients who had no cytogenetic response also received HSCT. Eleven patients (4.5%, Group A, N=8, Group B, N=3) failed to achieve complete hematological remission. The overall complete cytogenetic response (CCR) rate at 6 months after the treatment was better in Group B (89%) than in Group A (79%) with borderline significance (p=0.05, Fisher's exact test). However, the overall CCR rate at 12 months was 92% in both groups. At 12 months, MR3 was achieved in 61% and 64% of patients in Group A and Group B, respectively (p=0.69). Also, at 24 months, MR3 was achieved in 91% and 87% of patients in Group A and Group B, respectively. At 3 months, plans called for 8 and 45 patients to increase the dose of IM to 600 mg in Group A and B, respectively; however, only 4 and 27 patients followed the protocol. At 6 months, 10 and 55 patients were to increase the dose of IM to 600 mg in Group A and B, respectively; however, only 2 and 24 patients followed this protocol. The main reason was intolerance of IM. Among the patients who were to increase the dose at 3 and 6 months, 53% of those who could do according to the protocol achieved MR3 at 12 months, while only 16% of patients failed to increase (p=0.08). Eighty patients experienced drug discontinuation during 1 year. The incidence of discontinuation was 37% in Group B, whereas it was 29% in Group B (p=0.18). A substantial part of patients withdrew from this study; however, there was no difference between Groups (A 20%, B 21%). This is the first randomized study to compare two different dose escalation programs. The aggressive dose escalation program showed a better early cytogenetic response than the standard-dose escalation program, but, failed to evidence a better molecular response in a later period. Higher efficacy of high dose IM might be cancelled by the more frequently discontinuation of IM in this group. This study concluded that aggressive dose escalation is not recommended and careful management of drug dose according to patients' condition (residual leukemia, adverse effect, emotion) might be the best way for better outcome, which is applicable to new generation TKIs. Disclosures Miyamura: Nippon Shinyaku CO, LT: Honoraria; Pfizer Inc: Honoraria; Novartis Pharmaceutical: Honoraria; Alexion Pharmaceutical Inc: Honoraria. Usui:Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Research Funding. Nakaseko:BMS: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; NOVARTIS: Honoraria. Fujita:Chugai Pharmaceutical Co.,LTD: Honoraria. Okumura:Novartis Pharma: Honoraria. Hatta:Novartis Pharma: Honoraria. Naoe:Astellas Pharma Inc.: Research Funding; Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; Celgene K.K.: Honoraria, Research Funding; Amgen Astellas BioPharma K.K.: Honoraria; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties; TOYAMA CHEMICAL CO.,LTD.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; CMIC Co., Ltd.: Research Funding; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Pfizer Inc.: Research Funding.

Sustained Complete Molecular Response to Imatinib in Chronic Myeloid Leukemia (CML): a Target Worth Aiming and Achieving?.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 505-505 ◽  
Author(s):  
Dushyant Verma ◽  
Hagop M Kantarjian ◽  
Jenny Shan ◽  
Susan O'Brien ◽  
Amit Verma ◽  
...  
Keyword(s):  
Research Funding ◽  
Quantitative Polymerase Chain Reaction ◽  
Univariate Analysis ◽  
Chronic Phase ◽  
Cancer Center ◽  
Molecular Response ◽  
Event Free Survival ◽  
Long Term Outcome ◽  
Free Survival ◽  
Complete Molecular Response

Abstract Abstract 505 Background: Therapy with imatinib and other tyrosine kinase inhibitors leads to complete cytogenetic response (CCyR) in 80-90% of patients in chronic phase (CP) of CML, but most patients have residual disease documented by real-time quantitative polymerase chain reaction (PCR). Only a minority of patients achieve complete molecular response (CMR), as defined by undetectable levels of BCR-ABL fusion transcripts by PCR with sensitivity of at least 4.5 logs. Achieving CMR may offer the possibility of treatment discontinuation. Aims: To identify patients with sustained CMR (CMR of at least 6 months consecutively on 2 different dates) so as to define i) incidence of sustained CMR, ii) significance in long-term outcome (event-free survival, survival, transformation), and iii) predictive factors for CMR. Methods: We analyzed records of all patients with CML in early chronic phase (ie, within 12 months from diagnosis) treated with imatinib as frontline therapy at MD Anderson Cancer Center from July 2000 to Aug 2009. Major molecular response was defined as a BCR-ABL/ABL ratio of ≤0.05%, and CMR as undetectable transcripts in an assay with a sensitivity of at least 4.5 logs. Molecular responses were considered sustained only if they met the criteria for response in at least 2 consecutive assays separated over a period of at least 6 months. All patients were followed by PCR every 3 months for the first 1-2 years, then every 3-6 months. Rates of molecular response are reported on an intention-to-treat analysis. Results: 281 patients were included: 271 in CP and 10 in CP with clonal evolution at the time of diagnosis. The median age was 48 years (range 15-83), 119 (42%) were females, median CML duration 1 month (mo) (range 0-12). Seventy-three (26%) patients received an initial imatinib dose of 400 mg and 208 (74%) with 800 mg. The median follow-up is 65 mo (range 2-107) with 249 (89%) treated for over 12 mo, 225 (80%) for over 24 mo, 211 (75%) for over 36 mo, 154 (55%) for over 60 months, and 29 (10%) treated for over 96 mo. 55 (20%) have discontinued therapy (34 -12%-, because of resistance, and 21 -7%- because of intolerance). Overall, 248 (88%) achieved a CCyR, 80 (28%) a MMR without CMR, and 123 (44%) a CMR in at least one measurement. MMR was sustained in 95 (34%) and CMR in 84 (30%). The median time to CCyR was 3 mo (range 2-30), to sustained MMR 18 mo (range 6-78), and to sustained CMR 30 mo (range 6-84). The median event free survival was not reached for patients in CCyR with CMR/MMR without CMR/no MMR. Among patients who did achieve a CCyR, those that had a sustained CMR by 24 mo of therapy had an EFS of 100% at 5 yrs, compared to 96% for those with MMR but no CMR, and 86% for those with CCyR but no MMR (p=0.02). The rate of survival free from transformation to accelerated or blast phase at 5 yrs was 100% for those with CMR at 24 mo, compared to 96% for those with MMR but no CMR, and 91% for those with CCyR but no MMR (p=0.1). On univariate analysis, factors predicting sustained CMR were platelet count >450×109/L (p=0.001), CCyR at 3 mo (p=0.0005) and at 6 mo (p<0.0001). Conclusion: These results suggest that achieving a CMR is an important endpoint for patients with CML treated with imatinib as initial therapy. Treatment strategies that may increase the rate of sustained CMR should be investigated. Disclosures: Kantarjian: Novartis: Research Funding. Rios:Novartis: Consulting and speakers' bureau-honoraria . Cortes:Novartis: Research Funding.

T Cell Blast Phase (T-BP) of Chronic Myelogenous Leuikemia (CML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4560-4560
Author(s):  
Alfonso Quintás-Cardama ◽  
Hagop Kantarjian ◽  
Jorge Cortes
Keyword(s):  
T Cell ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Granulocytic Sarcoma ◽  
Cancer Center ◽  
Cell Phenotype ◽  
High Dose ◽  
Molecular Response ◽  
Abl Kinase ◽  
Extramedullary Disease

Abstract Approximately 65% of patients with CMP BP exhibit a myeloid phenotype, 30% a lymphoid, and 5% of cases have and undifferentiated or mixed phenotype. Most cases of lymphoid BP are of B-cell origin. Only anecdotal cases of T-BP have been reported. To evaluate the incidence and outcome of T-BP, we reviewed 410 patients with CML who underwent transformation to BP at M.D. Anderson Cancer Center between January 1999 and April 2007. Six cases (4 female) were diagnosed as having T-BP (incidence 1.5%). Three patients presented initially with T-BP whereas 3 other cases evolved to T-BP from chronic phase. The median time from diagnosis to transformation was 8 months (range, 0–72). The median age was 50 years (range, 24–66), median white blood cell count at presentation 20.5x109/L (range, 2.6–104), hemoglobin 11.2 g/dL (range, 10.6–13.6), platelet count 139x109/L (range, 20–295), peripheral blood blasts 6% (range, 0–100), and bone marrow blasts 20% (range, 2–88). All but 1 presented with extramedullary disease: 2 with lymphadenopathy, 2 with lymphadenopathy and mediastinal mass (including 1 also with pericardial tamponade), and 1 with splenomegaly, lymphadenopathy, and granulocytic sarcoma of the breast. Four patients had an immunophenotype consistent with byphenotypic T-cell/myeloid leukemia and 2 exhibited an exclusive T-cell phenotype. Three patients expressed a b2a2 BCR-ABL1 transcript (p210), whereas 1 carried b2a2+b3a2 (p210), 1 e1a2 (p190), and 1 expressed an e13b2+e14a2 (p210) transcript at the time of transformation but this switched to e1a2 (p190) during the course of dasatinib therapy. Three patients had failed prior therapies, including interferon-alpha (n=3), high dose imatinib (n=1), and matched-unrelated stem cell transplantation (SCT; n=1) at the time of transformation. Initial therapy for T-BP consisted of chemotherapy: hyper-CVAD in 3 patients (in 1 case with imatinib 600 mg daily), VAD in 1 patient, and a combination of idarubicin and ara-C in 2 cases (1 of them with imatinib 600 mg daily and dexamethasone). Only the 2 patients treated with chemotherapy and imatinib responded, achieving a complete cytogenetic response (CCyR) that lasted 3 and 14 months, respectively. Subsequent therapy in the remainder 4 patients consisted of high-dose imatinib (600–800 mg daily; n=4), which was administered for a median of 27 months (range, 0.5–87), dasatinib (n=1), autologous SCT (n=1), allogeneic SCT (n=1), and other chemotherapeutic regimens (n=4). One of the patients treated with imatinib (600 mg daily) achieved a complete molecular response (CMR) that is ongoing after 87 months of therapy. The patient treated with dasatinib (70 mg twice daily) achieved a CCyR. This patient presented the previously unreported K271R ABL kinase domain mutation prior to the start of dasatinib therapy. At the time of dasatinib failure, DNA expansion of specific clones followed by DNA sequencing detected the dasatinib-resistant mutations V299L and F317L in 80% and 20% of clones, respectively. Currently, 4 patients are dead while 2 are still alive, 1 in CMR receiving imatinib and 1 in CCyR after allogeneic SCT. In conclusion, T-BP is a rare variety of BP CML, which frequently exhibits extramedullary disease and high resistance to conventional chemotherapeutic regimens. Long-term responses can be achieved with ABL kinase inhibitors and/or allogeneic SCT.

High-Dose Imatinib Mesylate Treatment in Patients (Pts) with Previously Untreated Early Chronic Phase (CP) Chronic Myeloid Leukemia (CML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 999-999 ◽  
Author(s):  
Jorge Cortes ◽  
Moshe Talpaz ◽  
Susan O’Brien ◽  
Francis Giles ◽  
Mary Beth Rios ◽  
...  
Keyword(s):  
Standard Dose ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
P Value ◽  
High Dose ◽  
Free Survival ◽  
Clinical Observations ◽  
Pre Treatment ◽  
Grade 3

Abstract Imatinib has become the treatment of choice for most with CML. The standard dose (SD) for CP CML is 400 mg daily, but pre-clinical and clinical observations suggest that higher doses (HD) may be more effective. We have treated 222 with previously untreated CML in early CP with imatinib in 3 consecutive trials: one using SD imatinib (400 mg/day) (n=50; all entered in April 2001) and 2 subsequent trials using 400 mg twice daily (total dose 800 mg/day) (n= 172; from June 2001 until present). The 2 HD trials had identical inclusion criteria and will be considered together for this analysis. Pts followed for at least 3 months (mo) are evaluable (n=210) for this report (n=49 at 400mg, 161 at 800 mg). The median age was 48 years (range, 15 to 84); platelets were >450 x109/L in 71 pts (34%), 78 (37%) had peripheral blood (PB) blasts, and 11 (5%) had clonal evolution. Sokal risk group classification was good in 128 (61%) pts, intermediate in 61 (29%) pts, and poor in 21 (10%) pts. There was no difference in pre-treatment characteristics between the standard SD and HD groups. The results at 18 months are as follows: Response % Response p value* 400 mg/day 800 mg/day CR=Complete remission, Molecular Major=BCR-ABL/ABL <0.05%, Molecular CR=BCR-ABL undetectable (confirmed by nested PCR), *p value by log-rank Median follow-up (months) 36 19 Cytogenetic CR 81 96 0.0002 Cytogenetic Major 99 93 0.15 Molecular Major 47 67 0.0007 Molecular CR 8 24 0.02 Four pts treated with SD have transformed (3 to BP, 1 to AP) and 3 (2 to BP, 1 to AP) in the HD groups (p=0.05) (median time to transformation 11 mo, range 3 to 27). Estimated progression-free survival at 12 mo is 92% in the SD group and 99% in the HD group (p=0.42) (p=0.12 for the estimated transformation-free-survival, 94% and 99% for SD and HD at 12 mo). 4 have died (1 in SD and 3 in HD). Extramedullary toxicity was similar in the 2 groups, but myelosuppression was more common with HD, with grade ≥3 anemia, neutropenia and thrombocytopenia occurring in 7%, 39%, and 27% of pts receiving HD, respectively, and 4%, 20% and 12% of pts receiving SD. At 12 mo, the median actual dose for the HD group is still 800mg, with 40/112 (36%) evaluable having required dose reduction. This compares with 7/43 (14%) of those treated with SD. We conclude that high-dose imatinib results in higher rates of complete cytogenetic and molecular remissions, with some increase in myelosuppression.

Imatinib High Dose (800 mg): Results of a Phase II Trial of the GIMEMA (Gruppo Italiano Malattie Ematologiche Dell’Adulto) CML Working Party in Intermediate Sokal Risk Patients and Status-of-the-Art of an Ongoing Multinational, Prospective Randomized Trial of Imatinib Standard Dose (400 mg Daily) vs High Dose (800 mg Daily) in High Sokal Risk Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4776-4776
Author(s):  
Gianantonio Rosti ◽  
Fausto Castagnetti ◽  
Marilina Amabile ◽  
Nicoletta Testoni ◽  
Angela Poerio ◽  
...  
Keyword(s):  
Phase Ii ◽  
Standard Dose ◽  
Chronic Phase ◽  
Working Party ◽  
Great Majority ◽  
Observation Time ◽  
Phase Iii ◽  
High Dose ◽  
Molecular Response ◽  
Risk Patients

Abstract Imatinib has become the treatment of choice for CML. The standard dose (SD) for CP CML is 400 mg daily: results are less favourable in pts at high or intermediate Sokal risk vs low Sokal risk ones. In intermediate Sokal risk, the IRIS trial (Hughes et al NEJM 349:15, 2003 ) reported at 12 mos a complete cytogenetic response (CCgR- 0% Ph-pos) rate of 67% and a major molecular response (MMolR) rate of 45%. Pre-clinical and clinical data suggest that high doses (HD - 800 mg daily) of ima may be more effective. The GIMEMA CML Working party is conducting a phase II, multi-istitutional prospective study (serial n. CML/021) to investigate the effects of imatinib HD in intermediate Sokal risk. Between Jan, 2004 and May, 2005, 25 centers enrolled 82 pts (80 eval); median age 56 yrs (26–79). Pts evaluable at 3,6 and 12 mos are 80, 77 and 65, respectively. The median observation time is 12 mos. At 3 and 6 mos, 83% and 97% of the pts reached a stable CHR. At 6 mos, 86% obtained a CCgR and 53% of CCgR pts a MMolR (Bcr-Abl/Abl × 100 ratio &lt; 0.1%). At 12 mos, the CCgR rate was 90% and the MMolR rate was 57%. One patient progressed to accelerated/blastic phase. The compliance to HD treatment was good: at 3, 6 and 12 mos 55%, 52% and 52% of the pts received a median daily dose of imatinib &gt; 600 mg. Non hematopoietic AEs accounted for the great majority of dose reductions. The results of this trial further indicate that imatinib HD induces higher and more rapid responses in intermediate Sokal risk CML pts in early chronic phase, being superior to the results obtained with SD (IRIS) and in the range of the MD Anderson results (Kantarjian et al Blood 2004 103:2873). A second project is reserved to high Sokal risk CML pts in early CP: a multinational group, within EuropeanLeukemianet CML WP, is conducting a phase III trial (1:1) of imatinib 400 mg vs 800 mg. By July 31, 2005, 141 patients have been enrolled: GIMEMA (88 pts), Nordic CML Study Group (Sweden, Denmark, Norway and Finland) (25 pts), Turkey (25 pts) and Israel (3 pt).

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

Maintaining Imatinib ≥600 Mg Daily in the First 12 Months of Chronic Phase CML Treatment Is Associated with Superior Event-Free Survival at 5 Years.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1125-1125 ◽  
Author(s):  
Michael P Osborn ◽  
Susan Branford ◽  
Deborah L White ◽  
John F Seymour ◽  
Ruth Columbus ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Event Rates

Abstract Abstract 1125 Poster Board I-147 The Australasian Leukaemia and Lymphoma Group conducted a trial (TIDEL I) in 103 patients with newly diagnosed chronic phase CML, using imatinib 600 mg/day with dose escalation to 800 mg/day for suboptimal response. This was defined as failure to achieve (1) complete haematological response (CHR) at 3 months, (2) major cytogenetic response (MCR) at 6 months, (3) complete cytogenetic response (CCR) or molecular equivalent at 9 months, or (4) less than 0.01% (IS) BCR-ABL by RQ-PCR at 12 months. Here we report the outcomes with all surviving patients having been treated for at least 60 months. We aimed to determine whether the patient outcome at 60 months was predicted by the molecular response within the first 18 months of imatinib therapy. The outcomes for patients maintaining a dose of imatinib of ≥600 mg/day in the first 12 months was compared to those who were on a reduced dose for at least part of this time. Event-free survival (EFS) was defined as death from any cause, accelerated phase/blast crisis (AP/BC), and loss of CHR, MCR or CCR. The 103 patients included 66 males and 37 females with a median (±SD) age of 49 (±14) years. All patients had an ECOG performance status of 0-2 at enrolment. The 5-year EFS was 71%, transformation (AP/BC) free survival (TFS) was 95%, and overall survival was 87%. Of the 14 patients who died, 3 died in blast crisis, 2 from transplant-related complications, 8 from CML-unrelated causes, and the cause of death of 1 patient was unavailable. The annual rates of progression to AP/BC over 5 years were 3%, 1%, 0%, 1%, and 0%, while annual event rates were 13%, 8%, 8%, 1%, and 4%. CCR was achieved by 89% of patients by 60 months, while 72% achieved a major molecular response (MMR) by this time. In the first 12 months of treatment, 55% of patients maintained an imatinib dose of ≥600 mg/day (mean ±SD dose = 604 ±10 mg/day), while 45% were on <600 mg/day for at least part of this time (mean ±SD dose = 511 ±100 mg/day). EFS at 60 months was significantly higher in patients taking ≥600 mg/day compared with those who had been dose-reduced to <600 mg/day (89% vs 56%, P<0.001). Annual event rates for the ≥600 mg/day group were 6%, 2%, 2%, 0%, and 2%, while annual event rates for those on <600 mg/day were 14%, 16%, 16%, 8%, and 4%. By 60 months, 96% of patients who had been on ≥600 mg/day within the first 12 months had achieved CCR, while only 80% of those who had been on <600 mg/day had achieved this milestone (P<0.001). Log rank analysis of the achievement of MMR was also significant (P=0.03). Overall survival and TFS after 12 months were both similar between the dosing groups. There was no difference between the dosing groups' median age (50 vs 48 years, P=0.36) or Sokal score (1.04 vs 0.94, P=0.33) that may otherwise account for these results. The outcome was also determined for all patients dependent on the BCR-ABL levels at various assessment timepoints. Patients with a BCR-ABL level of <10% (IS) at 6 months (n=92) had an EFS of 78% at 60 months, while all of those with a level >10% (IS) (n=8) had an event (P<0.001). Patients with a level of ≤1% (IS) at 12 months (equivalent to CCR) (n=81) had an EFS of 75% compared with 25% (n=13) for those with levels >1% (IS) (P<0.001). At 18 months, a level ≤0.1% (IS) (n=58) conferred an EFS of 88%, while those who had failed to attain this depth of response (n=30) had an EFS of 60%. There was a significant difference in EFS between those who had achieved an MMR at 18 months and those who had achieved a CCR, but no MMR (88% vs 67%, P=0.03). In conclusion, our data suggest that patients maintaining a dose of ≥600mg in the first 12 months of imatinib therapy are more likely to achieve CCR and MMR, and superior EFS compared to those with a lower dose. This study also confirms that achieving an MMR by 18 months is associated with improved EFS. This emphasises the value of achieving a molecular response early in the treatment course, as well as adding weight to the evidence supporting the role of molecular monitoring in CML. Disclosures Branford: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. White:Novartis and Britol-Myers Squibb: Research Funding. Seymour:Bayer Schering: Consultancy, Membership on an entity's Board of Directors or advisory committees, Travel grants; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Grants. Catalano:Roche: Honoraria, Research Funding, Travel grants. Mills:Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding.

Old Age Affects Survival but Not Response in Philadelphia Positive (Ph+) Chronic Myeloid Leukemia (CML) Patients Treated with Imatinib (IM): A Study of the GIMEMA CML WORKING PARTY.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1118-1118
Author(s):  
Gabriele Gugliotta ◽  
Fausto Castagnetti ◽  
Francesca Palandri ◽  
Massimo Breccia ◽  
Marilina Amabile ◽  
...  
Keyword(s):  
Old Age ◽  
Research Funding ◽  
Age Groups ◽  
Chronic Phase ◽  
Working Party ◽  
Molecular Response ◽  
Free Survival ◽  
Intention To Treat ◽  
Age Related ◽  
Prognostic Importance

Abstract Abstract 1118 Poster Board I-140 Background The median age of an unselected population of Ph+ CML patients is close to 60 years. In the prognostic classifications (Sokal, Blood 1984; Hasford, JNCI 1998) that were elaborated before the introduction of IM, age was a significant and important prognostic factor. The most recent IM studies have not clarified the prognostic importance of age and IM therapy is still denied to several elderly patients. Aim to asses the relationship between age (less and more than 65 years) and outcome, in CML patients treated front-line in early chronic phase (ECP). Methods We analyzed the data of 559 previously untreated ECP patients who were assigned to receive IM 400 mg daily (76%) or 800 mg daily (24%) in three controlled, prospective studies of GIMEMA (Clin Trials Gov. NCT00514488 and NCT00510926; and an observational study of IM 400 mg). The median follow-up is currently 42 (extremes 1 – 64) months. There were 115 patients more than 65 years old (median age 71 years), while 444 (79%) were less than 65 years (median age 46 years). The proportion of patients who were treated with IM 800 mg daily was the same in both age groups. Results The cumulative complete cytogenetic and major molecular response rates were identical in the two age groups (88% vs 88% and 82% vs 83%, respectively). However, overall survival (86% vs 93%, p = 0.01), failure-free survival (72% vs 81%, p=0.03) and particularly event-free survival (calculated based on the intention-to-treat principle, where events were any failure [according to the European LeukemiaNet criteria – Baccarani, Blood 2006] and treatment discontinuation for any cause) (60% vs 71%, p=0.006) were significantly inferior in the older age group. All these difference were mainly due to comorbidities leading to more deaths in CP (table). Conclusions/Methods These data show that response to IM was not affected by old age. Survival curves were affected because of age-related complications and comorbidities. Age should never be a contraindication to IM treatment. Acknowledgments: European LeukemiaNet, COFIN, University of Bologna and BolognAIL. Disclosures Saglio: Novartis: Honoraria. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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.

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