Kinetics of Molecular Response with Different Tyrosine Kinase Inhibitors (TKI) Used As Frontline Therapy in Chronic Myeloid Leukemia-Chronic Phase (CML CP),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3784-3784 ◽  
Author(s):  
Kiran Naqvi ◽  
Hagop M Kantarjian ◽  
Rajyalakshmi Luthra ◽  
Elias Jabbour ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Research Funding ◽  
Transcript Level ◽  
Initial Therapy ◽  
Molecular Response ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Molecular Responses ◽  
Transcript Levels ◽  
Frontline Therapy

Abstract Abstract 3784 Background: TKI are standard therapy for patients with CML CP. Imatinib was first established as frontline therapy and more recently dasatinib and nilotinib have shown improved rates and speed of response. Early molecular response has been associated with improved long-term outcome (Blood 2009; 113: 6315), thus the kinetics and rates of molecular response are important predictors of long-term outcome. Aim: To determine the kinetics and rates of molecular response with different TKIs used as initial therapy for patients with CML CP. Methods: We evaluated all pts treated with frontline TKIs (imatinib standard dose or high dose, dasatinib and nilotinib) in consecutive or parallel trials. Cytogenetic and molecular responses were assessed at least every 3 months for the first 12 months, then every 6 months, and were defined using the recommendations of European LeukemiaNet. Molecular responses were defined using international scale. Survival was calculated by the Kaplan-Meier method. Results: Of the 485 pts treated, 73 received imatinib 400mg; 208 imatinib 800mg; 99 dasatinib, and 105 nilotinib. Median age was 48 years (15–86) and median time from diagnosis to TKI therapy was 1 mo (1–13). The median follow-up for each group were 109 months (mo) with imatinib 400, 69 mo with imatinib 800, 30 with dasatinib and 25 mo with nilotinib. Nineteen pts with clonal evolution, but otherwise in CP, were included. Sokal risk score was high in 7%, intermediate in 24% and low in 69%. Cumulative rates of complete cytogenetic response (CCyR) were: imatinib 400mg 87%; imatinib 800mg 91%; dasatinib 96%; and nilotinib 94%. The rate of MMR with imatinib 400mg was 73%, with imatinib 800mg 87%, dasatinib 86%, and nilotinib 88%. Rates of CMR (BCR-ABL/ABL ≤0.0032% IS) were 51%, 71%, 61% and 62%. Median time to achieve MMR and CMR were: imatinib 400mg, 12 mo (3–60) and 18 mo (3–60); imatinib 800mg, 6 mo (3–60) and 9 mo (3–60); dasatinib, 6 mo (3–36) and 12 mo (3–54), and nilotinib 6 mo (3–48) and 6 mo (3–42). The median transcript levels at 3, 6, 12, 18, 24 and 36 mo by treatment arm are shown in table 1. The rates of MMR and CMR at 36 mo for imatinib 400mg were 58% and 34%. Corresponding rates for imatinib 800mg were 87% and 59%; for dasatinib 87% and 54%; and for nilotinib 90% and 63%. We then assessed the probability of achieving MMR and CMR at 12 mo according to the BCR-ABL/ABL levels at earlier timepoints. Two of 9 (22%) evaluable pts with transcript level >10 at 3 mo achieved a MMR at 12 mo but none achieved a CMR. In contrast, 31/52 (60%) evaluable pts with transcript level >1–10 at 3 mo, achieved a MMR at 12 mo and 4 (8%) achieved a CMR. Similarly, pts with level >0.1–1 at 3 mo, 72/129 (56%) evaluable pts achieved a MMR and 29 pts (22%) a CMR at 12 months. For each individual TKI, a similar trend was noted where a higher transcript level (>10; >1–10; >0.1–1) at 3 mo was associated with a decline in achieving a MMR and CMR at 12 mo (MMR- imatinib 400mg: 0%; 50%; 67%, imatinib 800mg: 0%; 62%; 80%, dasatinib: 33%; 67%; 71%, nilotinib: 100%; 50%, 88%, CMR-imatinib 400mg: 0%, imatinib 800mg: 0%; 8%; 10%, dasatinib:0%; 17%; 29%, nilotinib: 0%; 0%; 32%). The probability of transformation to AP/BP by transcript levels at 3 mo (>10; >1–10; >0.1–1, ≤0.1) was 0%, 3%, 2% and 1% for the overall population, with similar trends for the different therapies. Conclusion: New TKI provide a faster improvement in molecular response among pts with CML CP receiving TKI as initial therapy. Early responses are equally predictive of long-term outcome across all treatment options. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; ChemGenex: ChemGenex is now Cephalon, Inc., Consultancy, Research Funding; Deciphera: Research Funding.

Disease Patterns for Patients (pts) with Chronic Myeloid Leukemia (CML) That Have BCR-ABL Transcript Levels > 10% At 3 Month of Therapy with Tyrosine Kinase Inhibitors (TKIs)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3757-3757
Author(s):  
Aziz Nazha ◽  
Hagop M. Kantarjian ◽  
Preetesh Jain ◽  
Elias J. Jabbour ◽  
Alfonso Quintás-Cardama ◽  
...  
Keyword(s):  
Research Funding ◽  
Strong Predictor ◽  
Chronic Phase ◽  
Transcript Level ◽  
Initial Therapy ◽  
Molecular Response ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Free Survival

Abstract Abstract 3757 Background: Response to TKIs in CML at 3 month is a strong predictor for long term outcome in CML patients treated with TKIs. Pts who do not achieve a BCR-ABL transcript level < 10% or a MCyR at 3 months have lower event-free survival (EFS) and perhaps overall survival (OS). However, pts have rarely changed therapy based on response at this early time points. The purpose of this analysis is to understand the patterns of disease progression and management in this group of patients. Patients and Methods: A total of 489 newly diagnosed CML pts that received initial treatment with TKIs: imatinib 400 mg daily (83) imatinib 800 mg daily (199), and second generation TKIs (2GTKIs) (207) in consecutive or parallel trials between 7/2000 and 6/2011 were included in this analysis. Cytogentic and molecular responses were evaluated every 3 month for the first year and then every 6 month. Event was defined as transformation to accelerated phase (AP) or blast phase (BP), loss of complete hematologic response (CHR), or loss of MCyR. Results: Among the 489 treated pts, 58 (12%) did not achieve a MCyR or BCR-ABL transcript level < 10 % at 3 months (26 pts (31%) received IM400, 19 (10%) IM800, and 13 (6%) 2GTKIs. Eleven of these pts (19%) had high sokal score at diagnosis (1 pt treated with imatinib 400, 7 with imatinib 800, 3 with 2GTKIs). By 6 months, 52/58 pts (90%) continued on their original therapy: 39 (67%) at the same dose and 19 (33%) with a decreased dose because of adverse events. No pt had a dose increase. Six pts had discontinued therapy by 6 month: 4 due to intolerance, 1 loss of CHR and 1 for progression to BP. At 6 month, 27 pts (47%) achieved MCyR or BCR-ABL transcript level < 10 %. At 12 months, 47 pts (81%) were still receiving their initial therapy, 11 pts (19%) had discontinued their initial TKI: 6 due to intolerance, 1 loss of CHR, 2 for progression to BP, and 2 for resistant disease. After a median follow up of 95 months, 17 pts (29%) continue to receive their initial therapy and their current disease status are: complete cytogenetic response (CCyR) in 14 (82%), 2 (12%) lost their CCyR, and 1(6%) pt who never achieve any cytogenetic or molecular response and remains in chronic phase on the same dose of imatinib for over 8 years. Among these 17 pts, 11 (65%) have MMR, 2 (12%) with MR4.5, and 4 (24%) have lost MMR (2 of them with loss of CCyR). The 5 years OS, EFS and transformation-free survival (TFS) for the patients who did not achieve any response at 3 month was 88%, 77%, and 94%, respectively. The OS, EFS, and TFS for the patients who subsequently achieved a response (MCyR or BCR-ABL transcript level < 10 %) at 6 month was 100%, 66%, and 95%, respectively vs those who continued to have no response 79%, 95%, and 100%, respectively (P = 0.17, 0.07, 0.99, respectively). Conclusions: Although BCR-ABL transcript level at 3 month may predict long-term outcome of pts with CML treated with TKIs, this represents a static, one-time measure. Assessing the response at 6 months of pts with poor response at 3 months may provide a better predictor of long term outcome. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

The BCR-ABL Transcript Levels At 3 and 6 Months Predict the Long-Term Outcome of Chronic Myeloid Leukemia Patients Treated Frontline with Imatinib Mesylate: A Gimema CML WP Analysis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1678-1678
Author(s):  
Fausto Castagnetti ◽  
Gabriele Gugliotta ◽  
Massimo Breccia ◽  
Giorgina Specchia ◽  
Elisabetta Abruzzese ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Roc Curves ◽  
Molecular Response ◽  
Advisory Committees ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Free Survival ◽  
Transcript Levels

Abstract Abstract 1678 Background. Imatinib mesylate (IM) is the therapeutic standard for chronic myeloid leukemia (CML), but nilotinib and dasatinib, at least in selected patients, have the potential to replace it. The early prediction of poor outcome is important to optimize the treatment strategy. In IM-treated patients, BCR-ABL transcript levels according to the International Scale (IS) > 10% at 3 and > 1% at 6 months were able to identify high-risk groups (Marin et al, JClinOncol 2011; Hanfstein et al, Leukemia 2012). Similar analysis were performed within the IM arms of the ENESTnd trial (Hochhaus et al, EHA 2012) and the DASISION trial (Jabbour et al, EHA 2012). Methods. To investigate the prognostic impact of BCR-ABLIS levels at 3 and 6 months on the future response status and the long-term outcome of CML patients treated frontline with IM, we analyzed 559 patients enrolled within 3 trials of the GIMEMA CML WP (ClinTrialsGov NCT00514488/NCT00510926, observational trial CML023). Patients with evaluable QPCR sample at 3 and 6 months: 487/559 (87%) and 492/559 (88%), respectively. Definitions: major molecular response (MMR): BCR-ABLIS ratio <0.1%; molecular response with 4.0-log reduction (MR4.0): BCR-ABLIS <0.01%; failures: according to 2009 ELN recommendations. The rate of complete cytogenetic response (CCgR) and MMR at 1 year, the rate of MR4.0 at 2 years, the failure-free survival (FFS), the progression-free survival (PFS) and the overall survival (OS) according to the BCR-ABL transcript levels (≤10% vs >10 and ≤1% vs >1%) at 3 and 6 months were analyzed. Patients with events or censored within 3 or 6 months were excluded from the respective analysis. Receiver operating characteristic (ROC) curves were used for descriptive purposes. Results. Median age: 52 years (range 18–84). IM dose: 76% 400mg, 24% 800mg. Sokal score: 39% low, 39% intermediate, 22% high; EUTOS score: 93% low, 7% high. Median follow-up: 76 months (range: 7–99); 95% of patients had at least 5-year observation. BCR-ABLIS at 3 months: ≤1% in 336/487 (69%), >1% to ≤10% in 120/487 (25%) and >10% in 31/487 (6%). BCR-ABLIS at 6 months: ≤1% in 425/492 (86%), >1% to ≤10% in 54/492 (11%) and >10% in 13/492 (3%). Responses and outcomes according to transcript levels are presented in table 1. Patients with BCR-ABLIS >10% at 3 months achieved inferior CCgR and MMR rates at 1 year and inferior MR4.0 rate at 2 years, but the long-term outcome was comparable to patients with transcript levels < 10%. On the contrary, a BCR-ABLIS >1% at 3 months was associated, not only to lower subsequent response rates, but also to significantly inferior FFS, PFS and OS. The BCR-ABLIS levels able to predict for FFS, PFS and OS with maximal sensitivity and specificity (ROC curves) were 1.9%, 0.8% and 0.8%, respectively. Results were similar, with small differences, in the 6-month analysis. Conclusions. In a multicentric nationwide experience, the proportion of patients with BCR-ABLIS transcript levels >10% at 3 and 6 months was low. The risk distribution and the proportion of patients treated with high-dose IM may explain, at least in part, the differences with other published reports. At 3 and 6 months, a BCR-ABLIS cutoff of 1% was a reliable surrogate marker of response and outcome. A transcript level >10% identified a smaller cohort with inferior responses, but failed to predict the long-term outcome. A BCR-ABLIS level >1% at 3 and 6 months represents a warning, requiring a close monitoring. A switch to 2nd generation tyrosine kinase inhibitors should be considered. Acknowledgments. University of Bologna, BolognaAIL, COFIN, Fondazione Carisbo. Disclosures: Castagnetti: Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Novartis Pharma: Consultancy, Honoraria, Speakers Bureau. Gugliotta:Novartis: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria. Breccia:Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Abruzzese:Bristol Myers-Squibb and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavazzini:Novartis Pharma: Honoraria; Bristol Myers Squibb: Honoraria. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; ARIAD: Consultancy. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Martinelli:Bristol-Myers-Squibb: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Rosti:Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau.

scholarly journals Frequency and Impact of Molecular Response’s with Nilotinib (Tasigna) in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase (CML-CP)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3156-3156
Author(s):  
Naval Daver ◽  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Elias Jabbour ◽  
Sherry Pierce ◽  
...  
Keyword(s):  
Research Funding ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Landmark Analysis ◽  
Intent To Treat ◽  
Dose Reductions

Abstract Background: Nilotinib is a BCR-ABL tyrosine kinase inhibitor with approximately 50-fold higher inhibitory activity than imatinib in preclinical studies. Aim: We initiated a phase II study (in 2005) to evaluate the efficacy of frontline nilotinib in pts with newly diagnosed CML-CP. The primary objective of this report was to estimate major molecular response (MMR) and complete molecular response (CMR: minimum 100,000 ABL copies) rates with prolonged follow-up, and the impact of MMR and CMR on long-term outcome. Methods: Pts with Ph-positive or BCR-positive CML in early CML-CP [i.e., time from diagnosis 12 months] with <1 month of prior interferon-alpha and/or imatinib were eligible. Nilotinib was initiated at a dose of 400 mg twice daily. Results for CCyR and MMR are reported as intent-to-treat unless specifically annotated as response among evaluable pts (eval). Results: 140 pts have been treated as of August 1, 2014. Herein we focus on the initial 109 pts who have a minimum follow-up of 12 months. The median (med) follow-up for these 109 pts is 52.2 months (range, 0.9 to 108.0+). The med age was 50 years (range, 17 to 86). 73% of pts had Sokal low risk. 17 (16%) had received imatinib for <1 months (med 18 days; range, 5 to 29 days). Overall, 92% (100/109) pts achieved a complete cytogenetic response [CCyR] with a med time to CCyR of 2.9 months (range, 2.1 to 8.1+). The rates of CCyR at 3, 6, 12 and 18 months were 80% (eval:83%), 86% (eval:95%), 83% (eval:99%), and 77% (eval:100%), respectively. Overall, MMR and CMR were achieved in 90% (98/109) and 45% (49/109) of the pts. Med time to MMR and CMR was 3.3 months (range, 2.4 to 48.0+) and 23.1 months (range, 3.2 to 86.0+), respectively. BCR-ABL/ABL at 3 months was <10% in 94% (eval:100%) and <1% in 89% (eval: 94%). BCR-ABL/ABL at 6 months was <1% in 81% (eval:89%) and <0.1% in 65% (eval:72%) in pts evaluated at these time points. MMR was observed in 65% (eval:72%) at 6 months, 71% (eval:87%) at 12 months, and 70% (eval:90%) at 18 months. CMR was observed in 9% (eval:11%) at 6 months, 14% (eval:17%) at 12 months, and 15% (eval:19%) at 18 months. We further analyzed the association between CCyR and molecular response (Table 1). For example, among the 84 pts who were in CCyR at 18 months: MMR was achieved in 90% of these pts including MR3 in 31%, MR4 in 13%, MR4.5 in 27%, and CMR in 19%. Estimated 3-year and 5-year overall survival (OS) is 98% and 91%, respectively. Estimated 3-year and 5-year failure-free survival (FFS) is 82% and 73%, respectively. On an intent-to-treat analysis the FFS among pts who achieved CMR was superior to those who did not achieve CMR (P<0.001, respectively). On a landmark analysis, which included only those pts who received nilotinib for a minimum of 24 months (med time to CMR among pts who achieved CMR=23.1 months) the FFS among pts who achieved CMR was superior to those who did not achieve CMR (P=0.008) (Figure 1). Dose-reductions were performed in 41 (38%) pts: 30 pts required 1 dose-reduction and 11 pts required 2 or more dose-reductions. The most frequent reasons for dose-reductions included increased liver enzymes (n=8), rash (n=5), pain/arthralgia (n=4), cardiac and QTc (n=4), fatigue (n=5), and neutropenia (n=2). The actual med dose remains 800 mg daily. 29 (27%) pts are off study due to toxicity in 8 (cardiac=3, liver enzymes=4, fatigue=1), inadequate response in 5 (3 never achieved adequate and 2 lost adequate response), progression to blast-phase in 3, death in 5 (all 5 non-CML related causes), 8 due to pt choice (financial=1, non-compliance=3, pt choice=1) Conclusion: Nilotinib 400 mg twice daily is very effective. The cumulative rates of CCyR, MMR and CMR were 92%, 90%, and 45%, respectively. CMR rates continue to improve with long-term follow-up. Attainment of CMR is associated with improved long-term outcome. Table 1: Molecular response rates among pts who achieve CCyR CCyR MR3 but not MR4 MR4 but not MR4.5 MR4.5 but not CMR CMR No MMR 3 months 87/105 (83%) 39/87 (45%) 5/87 (6%) 8/87 (9%) 2/87 (2%) 33/87 (38%) 6 months 94/99 (88%) 35/94 (38%) 6/94 (6%) 20/94 (21%) 10/94 (11%) 23/94 (24%) 12 months 90/91 (99%) 38/90 (42%) 3/90 (3%) 23/90 (26%) 15/90 (17%) 11/90 (12%) 18 months 84/84 (100%) 26/84 (31%) 11/84 (13%) 23/84 (27%) 16/84 (19%) 8/84 (10%) PCyr, partial cytogenetic response; Min, mimimal; Inev, inevaluable; IM, insufficient metaphase Figure 1: FFS CMR versus no CMR by landmark analysis for pts who received at least 24.0 months of nilotinib Figure 1:. FFS CMR versus no CMR by landmark analysis for pts who received at least 24.0 months of nilotinib Disclosures Daver: Novartis: Research Funding. Jabbour:Novartis: Advisory board membership Other, Research Funding. Cortes:Novartis: Advisory Board membership Other, Research Funding.

scholarly journals Updating Long-Term Outcome of Intermittent Imatinib (INTERIM) Treatment in Elderly Patients with Ph+-CML

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1794-1794 ◽  
Author(s):  
Domenico Russo ◽  
Giovanni Martinelli ◽  
Michele Malagola ◽  
Valeria Cancelli ◽  
Cristina Skert ◽  
...  
Keyword(s):  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Residual Disease ◽  
Chronic Obstructive ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Term Outcome ◽  
Long Term Outcome

Abstract BACKGROUND: The INTERIM study (ClinicalTrials.gov NCT 00858806) showed that in elderly (> 65 years) Ph+ CML patients selected for a stable complete cytogenetic response (CCgR) lasting > 2 years, the policy of intermittent imatinib treatment (one month on/one month off) may affect the markers of residual disease (CCgR and major molecular response, MMR or MR3.0), but not the clinical outcomes (overall survival and progression-free survival) (Russo D et al, Blood 2013; 121(26):5138-44). AIMS: To update the results of the INTERIM Study, with a follow up ≥ 5 years. METHODS: After 4 years of follow up, patients continouing INTERIM treatment were monitored with peripheral blood RT-Q-PCR every 3 months according to the ELN-2013 guidelines. RESULTS: At 48thmonth, out of 76 patients enrolled in the INTERIM study, 13 (17%) had lost CCgR and MMR, 14 (18%) had lost MMR only and 50 patients (75%) continued INTERIM. The patients who had lost CCgR and/or MMR resumed imatinib continuously and all of them regained the CCgR and the MMR, within 3 to 12 months. No patient progressed to accelerated or blastic phase, or developed clonal chromosomal abnormalities in Ph+ cells, or BCR-ABL mutations. No patient complained of new or more severe side effects during the months “on”. After a follow up ≥ 5 years, 45/76 (59%) enrolled patients are on INTERIM, with a probability of maintaining intermittent administration of 59% (95% CI: 46-69). No patient lost the CCgR and only 9 additional patients lost the MMR while on intermittent treatment. All these patients resumed continuous imatinib treatment and regained the MMR. Thus, at ≥ 5 years, the probability of maintaing CCgR is 80% (95% CI 68-87) and the probability of maintaining the MMR is 61% (95% CI: 48-71). From start of INTERIM, 6 patients died but no deaths were related to CML progression (3 cases of other non haematological neoplasms, 1 stroke, 1 myocardial infarction, 1 chronic obstructive pulmonary disease).The PFS at ≥ 5 years is 94% (95% CI: 89-100) CONCLUSIONS: In summary, with a follow up ≥ 5 years, intermittent imatinib administration (INTERIM) confirmed to be safe, to produce a reversible increase of residual molecular disease in about one third of patients, but not to affect the long-term outcome. Aknowledgments: This work was supported in part by EuropeanLeukemiaNet (contract LSHC-CT-2004-503216) through the European Treatment and Outcome Study (EUTOS), supported by Novartis Oncology Europe, and COFIN 2009 Disclosures Russo: Celgene: Research Funding; Gilead: Research Funding; Novartis: Consultancy. Martinelli:Novartis: Speakers Bureau; Bristol-Meyers and Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Soverini:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria; Ariad: Consultancy, Speakers Bureau. Turri:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria. Castagnetti:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria. Breccia:novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy. Abruzzese:Novartis: Consultancy. Tiribelli:Novartis: Consultancy, Honoraria; Bristol-Meyers and Squibb: Consultancy, Honoraria. Rosti:Consultant: Consultancy, Speakers Bureau; Bristol-Meiers Squibb: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau.

Long-Term Outcome of 335 Adult Patients Receiving Different Schedules of Imatinib and Chemotherapy as Front-Line Treatment for Philadelphia-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 173-173 ◽  
Author(s):  
Heike Pfeifer ◽  
Nicola Goekbuget ◽  
Christian Völp ◽  
Andreas Hüttmann ◽  
Michael Lübbert ◽  
...  
Keyword(s):  
Treatment Outcomes ◽  
Research Funding ◽  
Molecular Response ◽  
Line Treatment ◽  
Newly Diagnosed ◽  
Front Line ◽  
Prolonged Administration ◽  
Term Outcome ◽  
Long Term Outcome

Abstract Abstract 173 Imatinib (IM) in combination with either of a variety of chemotherapy regimens has become the mainstay of front-line treatment for younger patients with Ph+ ALL, followed by allogeneic SCT as a curative treatment option. Complete remission (CR) rates generally exceed 90% and overall treatment outcomes have improved as judged on the basis of phase II trials, but there is a paucity of long-term outcome data obtained from a large group of prospectively evaluated patients. Moreover, the impact of different front-line IM schedules on the outcome of patients undergoing allogeneic stem cell transplantation in first CR (CR1) as opposed to non-transplanted patients has not been thoroughly evaluated. We previously reported the results of a GMALL study comparing two alternating and concurrent schedules of IM and chemotherapy in successive patient cohorts (A1 and A2, respectively)(Wassmann et al, Blood 2006;108:1469). In a subsequent cohort (A3), IM was started simultaneously with induction chemotherapy according to the GMALL protocol 07/03, i.e. immediately after confirmation of the presence of a Philadelphia chromosome and/or bcr-abl translocation and completion of prephase therapy. We here report the long-term results of a prospective multicenter study of the GMALL study group including a total of 335 patients with newly diagnosed Ph+ ALL who received IM given at a single daily oral dose of 600 mg within 3 successive treatment cohorts. A1: IM administered between induction (IND) and first consolidation cycles (CONS1) and again after CONS1 (n=51); A2: IM given during the second half of IND and then continued throughout CONS1 until SCT (n=105); A3: IM initiated together with start of induction chemotherapy and continued throughout CONS1 until SCT (n=179). Minimal residual disease (MRD) was serially assessed by quantitative RT-PCR, mutational analyses was performed by D-HPLC and direct sequencing. The median age of all patients was 43 years (17-65 y), 57 (17%) patients were 55 years of age or older, 147 (44%) male and 182 (56%) female. CR rates in cohorts A2 and A3 were 89,4% and 85.7%, induction deaths occurred in 5.8% and 11.3% of patients, treatment failure was observed in 4.8% and 3% of pts., respectively. Initial responses are not reported for cohort A1 as only pts. already in CR or PR were eligible for study entry at this stage of the trial. The molecular response rate based on PCR negativity for bcr-abl transcripts after CONS1 was superior in cohort A3 with 33% (26/79) as compared to 12.5% (5/40) and 4.2% (2/47) in cohorts A2 and A1, respectively (p=0.01). Overall treatment outcome improved with earlier initiation and more prolonged administration of IM in the three successive patient cohorts: Overall survival (OS) at 4 years was 31%, 40% and 50% in cohorts A1, A2 and A3, respectively. There was a trend towards lower rates of pre-transplant relapse or treatment discontinuation of patients in CR in cohort A3 (4% and 1.1%, respectively) compared to cohorts A2 (8.7% and 5.8%) or A1 (11.8% and 5.9%). To date, 219 patients (66.4%) underwent SCT in CR1 (A1: n=39; A2: n=74; A3: n=106), with a median age of 39.5 years. The 3 year probability of DFS of pts. in cohort A3 who received myeloablative conditioning regimens combining TBI with cyclophosphamide or etoposide was 72%. DFS was not significantly different between matched sibling and matched unrelated donor SCT. The incidence of relapse after SCT was substantially lower among patients in cohort A3 (11.3%) than those in A2 (24.3%) or A1 (30.8%). Similarly, there was a trend to lower non-relapse mortality after SCT in A3 (20.8%) compared to A2 (25.7%) or A1 (33.3%). For all pts. transplanted in CR1 irrespective of treatment cohort, median OS was 57% after 3 yrs. and 52% after 7 yrs. Patients who did not undergo SCT in CR1 had a dismal outcome, with a median OS of 9.4 months and 14% alive after 3 years. In conclusion, earlier and more prolonged administration of IM in conjunction with chemotherapy is associated with superior treatment outcomes after SCT in newly diagnosed pts. with Ph+ ALL who are considered eligible for allogeneic SCT. SCT in CR1 remains the treatment of choice even in patients who achieve a good molecular response to initial therapy. Reducing induction as well as post-transplant mortality could have the greatest impact on further improving OS and DFS. Disclosures: Ottmann: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

Seven Year Follow up of Chronic Myeloid Leukemia (CML) Patients Treated with Nilotinib 400 Mg Twice Daily - a Single Center Study at MDACC

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2796-2796
Author(s):  
Binsah Susan George ◽  
Hagop M Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Farhad Ravandi ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Patient Characteristics ◽  
Initial Therapy ◽  
Molecular Response ◽  
Event Free Survival ◽  
Free Survival ◽  
Frontline Therapy

Abstract Introduction: Nilotinib is a second generation Tyrosine kinase inhibitor, approved for the treatment of CP-CML after imatinib failure and as frontline therapy. Nilotinib was first used as initial therapy in 2005 and the early results showed deep and fast response rates (JCO 2010 Jan 20; 28(3):392-7). The ENESTnd later showed response rates to be superior to those obtained with imatinib. Here we report the long-term follow-up results of the first trial of nilotinib frontline therapy for CML-CP. Objective: To assess the long term outcome of patients with CML treated with nilotinib as initial therapy. Methods: We analyzed a total of 148 patients (≥17 years old) with newly diagnosed CML who were enrolled between July 2005 and November of 2014 at MDACC on a clinical trial (NCT00129740) of nilotinib 400mg twice daily. Patients were assessed for cytogenetic and molecular response rate (measured every 3 months for the first year, every 6 month thereafter), overall survival (OS), event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS) using Kaplan-Meier method. Results: The baseline patient characteristics are shown on table 1. The median age was 51 years, with 20 patients aged ≥65. High sokal risk score was seen in 17% patients, and 17% of patients were in accelerated phase (AP) at diagnosis. Rates of complete cytogenetic response (CCyR) were: 78% at 3 months, 89% at 1 year, 94% at 5 years, and 97% at 7 years. Rates of MMR were 76% at 1 year, 87% at 5 years, and 93% at 7 years. Corresponding rates of MR4.5 were 39%, 76% and 83%, respectively. With a median follow-up of 59 months, 51 (34%) patients have discontinued therapy. Reasons for treatment discontinuation includes: 9 (6%) with non- cardiac toxicity including 3 with grade ≥3 increase in liver function tests, 2 with acute pancreatitis, 1 with renal failure, 1 with grade ≥2 increase in creatinine, 1 with grade ≥3 elevated lipase, 1 with headache; 6 (4%) with cardiovascular events including 2 myocardial infarction, 1 positive stress test, 1 stroke, 1 pericarditis, and 1 atrial fibrillation; 8 (5%) transformed to blast phase; 5 (3%) for resistance in CP; and 16 (10%) for other reasons including; patient request (n=8), patient noncompliance (n=6), insurance reasons (n=2); and 5 because of death due to unrelated reasons. After nilotinib discontinuation, patients received dasatinib (n=13), imatinib (n=8), bosutinib (n=3), ponatinib (n=2), rebastinib (n=1), chemotherapy plus dasatinib (n=3), AML-like chemotherapy (n=1), hydroxyurea (n=1), stem cell transplant (n=1), and unknown or none (because of lost to follow up, insurance or noncompliance (n=11). At 1, 5 and 7 year projected OS was 98%, 88% and 88%, respectively; EFS was 91%, 83% and 77%, respectively; TFS was 95%, 89% and 87%, respectively; and FFS was 82%, 70% and 57%, respectively, shown in figure (1,2,3) Conclusion: The long-term results from this study of nilotinib as frontline treatment of newly diagnosed CP-CML confirm the excellent results achieved with rapid and deep cytogenetic and molecular response, translating into very favorable long-term survival endpoints. Use of nilotinib in this setting has a favorable toxicity profile confirming its value as frontline therapy for CML-CP. Table 1. Patient Characteristics Median [range] or No. (%) Patients, n 148 Age, years, median [range] 51 [17-86] Age ≥65 years 20 (13) Follow up in months 59 [0-113] Patients ≥ 65 20 Male 91 (61) CP-CML 121 (82) AP- CML 27 (17) Risk score, n (%) - Low - Intermediate - High 101 (68) 21 (14) 26 (17) WBC (x109/L) 57 [0.8-342] PB Blast, % 0 [0-20] BM Blast, % 2 [0-25] PB Basophil, % 3 [0-13] BM Basophil, % 2 [0-13] Splenomegaly,cm 0 (0-30) Clonal evolution at diagnosis 3 (0.2) Patient Characteristics: Table (1) Figure 1. Overall survival Figure 1. Overall survival Figure 2. Event-Free Survival Figure 2. Event-Free Survival Figure 3. Transformation-free survival Figure 3. Transformation-free survival Disclosures Cortes: Novartis: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding.

scholarly journals Prognostic Significance of Transcript-Type BCR‐ABL1 in Chronic Myeloid Leukemia

2020 ◽  
Vol 12 (1) ◽  
pp. e2020062
Author(s):  
Matteo Molica ◽  
Elisabetta Abruzzese ◽  
Massimo Breccia
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Prognostic Significance ◽  
High Rate ◽  
Long Term Outcomes ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Molecular Responses

Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene. In more than 95% of CML patients, the typical BCR-ABL1 transcript subtypes are e13a2 (b2a2), e14a2 (b3a2), or the simultaneous expression of both. Other less frequent transcript subtypes, such as e1a2, e2a2, e6a2, e19a2, e1a3, e13a3, and e14a3, have been sporadically reported. The main purpose of this review is to assess the possible impact of different transcripts on the response rate to tyrosine kinase inhibitors (TKIs), the achievement of stable deep molecular responses (s-DMR), the potential maintenance of treatment-free remission (TFR), and long-term outcome of CML patients treated with TKIs. According to the majority of published studies, patients with e13a2 transcript treated with imatinib have lower and slower cytogenetic and molecular responses than those with e14a2 transcript and should be considered a high-risk group who would mostly benefit from frontline treatment with second-generation TKIs (2GTIKIs). Although few studies have been published, similar significant differences in response rates to 2GTKIs have been not reported. The e14a2 transcript seems to be a favorable prognostic factor for obtaining s-DMR, irrespective of the TKI received, and is also associated with a very high rate of TFR maintenance. Indeed, patients with e13a2 transcript achieve a lower rate of s-DMR and experience a higher probability of TFR failure. According to most reported data in the literature, the type of transcript does not seem to affect long-term outcomes of CML patients treated with TKIs. In TFR, the e14a2 transcript appears to be related to favorable responses. 2GTKIs as frontline therapy might be a convenient approach in patients with e13a2 transcript to achieve optimal long-term outcomes.  

FLT3 Inhibitor Therapy for Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML): Impact On Survival According to FLT3 Status.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1026-1026 ◽  
Author(s):  
Naveen Pemmaraju ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Guillermo Garcia-Manero ◽  
Borthakur Gautam ◽  
...  
Keyword(s):  
Research Funding ◽  
Initial Therapy ◽  
Inhibitor Therapy ◽  
Clinical Activity ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Flt3 Inhibitor ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Impact On Survival

Abstract Abstract 1026 Poster Board I-48 Background: FLT3 mutations (ITD or D835 point mutation) are frequently observed in patients (pts) with AML and they confer an adverse prognosis, particularly among pts with diploid karyotype. This has made FLT3 an important target for drug development in AML. Several FLT3 inhibitors are currently being developed (eg, sorafenib, PKC-412, AC-220, CEP-701, IMC EB10, sunitinib). Results from early trials with many of these agents suggest they have clinical activity in the treatment of MDS and AML, although most responses are represented by a marked decrease in blast counts, with few complete remissions(CR). Whether these responses ultimately improve long-term outcome of pts, and whether they may be particularly beneficial for pts with FLT3 mutations compared to those with FLT3 wild-type (WT) is being investigated. Aims: To ascertain outcomes of patients given treatment with FLT3 inhibitors, alone or in combination with other therapies, and to compare outcomes in those patients with FLT3 mutations (ITD or D835) versus those with FLT3-WT. Methods: We reviewed the records of patients with MDS and AML who were enrolled on clinical trials with FLT3 inhibitors at our institution. We compared patient outcomes in those who received a FLT3 inhibitor in both FLT3 positive and FLT3 negative patients. Pts were classified as receiving FLT3 inhibitors 1) as part of their initial therapy, 2) as first salvage, or 3) as second salvage or beyond. Results: A total of 128 pts were included: 51 (40%) with FLT3-WT, 56 (44%) with FLT3-ITD, 11 (9%) with D835, and 10 (8%) had both FLT3-ITD and D835. The overall median age was 62 yrs (range, 17-88); by FLT3 status, median age was 70 yrs (35-88) for FLT3-WT pts and 58 yrs (17-81) for FLT3 mutated. Sixty-four pts (50%) were female. Twenty-three (18%) pts received FLT3 inhibitors as part of their induction therapy (18 FLT3-WT, 5 FLT3 mutated; median age 74 yrs); 22 (17%) as first salvage (4 FLT3-WT, 18 mutated; median age 67 yrs); and 83 (65%) as second or later salvage (29 FLT3-WT, 54 mutated; median age 59 yrs). Nine pts overall, all of whom were FLT3 mutated, achieved either CR (n=6) or CRp (n=3) with FLT3 inhibitors. Eight of the nine CR/CRp have been lost with a median CR duration of 8 months (mo) (3-12+). After a median follow-up of 3.5 mo, 115 (90%) pts have died, including 47 (92%) FLT3-WT, and 68 (88%) FLT3 mutated. The median survival is 3.8 mo for the total population. Survival by mutation status and timing of FLT3 inhibitor therapy is presented in table 1. Conclusions: Despite the inferior outcome expected for pts with FLT3 mutations, and the low rate of CR/CRp with FLT3 inhibitors, these results suggest that therapy with FLT3 inhibitors has the potential to improve the outcome of pts with FLT3 mutations. Additional studies incorporating these agents in AML therapy are warranted. Disclosures: Off Label Use: Sorafenib has not been FDA approved for use in MDS and AML. Kantarjian:Novartis: Research Funding. Cortes:Ambit: Research Funding; Novartis: Research Funding; ImClone: Research Funding.

Long-Term Outcome Following B-Cell Depletion Therapy with Rituximab In Children and Adults with Immune Thrombocytopenia (ITP)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 72-72 ◽  
Author(s):  
Vivek L. Patel ◽  
Matthieu Mahévas ◽  
Roberto Stasi ◽  
Susanna Cunningham-Rundles ◽  
Bertrand Godeau ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Initial Response ◽  
Response Rates ◽  
Advisory Committees ◽  
Term Outcome ◽  
Long Term Outcome ◽  
One Year

Abstract Abstract 72 Background: Studies of B-cell depletion using Rituximab in adults with ITP report responses lasting at least one year in almost all of the 30–40% of patients with complete responses (CR: platelet count >150 × 109/l) and also a small fraction of patients with partial responses (PR: platelet count 50–150 × 109/l). However data describing patients with ITP who are relapse-free and off-treatment beyond 1–2 years from initial Rituximab are almost entirely anecdotal and comparable response data are even less available for children. This study assessed the duration of unmaintained platelet response following rituximab treatment in 72 adults and 66 children with ITP, all of whom had had at least an initial response to rituximab. Long-term outcome was estimated from these data. Methods: Seventeen published studies including 486 patients, 376 adults and 110 children, were used to obtain the initial response rates to standard-dose rituximab treatment (375mg/m2 weekly for 4 weeks) in adults and children. Only 1 included study did not use the standard dose of rituximab. The Godeau study (Blood, 2008) was used to estimate the one-year response rate in adults with ITP. Only those adults whose responses persisted at least one year had follow up assessed whereas children who demonstrated even ephemeral responses were included. Only verified counts were used in this IRB-approved multicenter study. Results: 138 subjects with CR's or PR's after rituximab were included. All patients had starting platelet counts <30×109/l and 131 (95%) had ITP of > 6 months duration. Thirty-three (24%) had undergone splenectomy. Using the data from prior publications to obtain the initial response rates, children had a 56% initial response rate to rituximab treatment and adults had a 57% rate. Taking initial responders and then using the Godeau data for adults and Kaplan-Meier analysis of our data for children, 38% one-year response rates were obtained for both children and adults treated with rituximab. Both age groups also showed remarkable similarity at two years with 30% relapse-free response rates. However, all of the 26 eligible children maintained their response beyond two years whereas adults continued to relapse. Therefore the five-year response rate was 30% for children and only 21% for adults. Sex, duration of ITP, and age among adults did not affect long-term outcome. The rate of relapse was almost identical for splenectomized patients and non-splenectomized ones but the splenectomized patients appeared to relapse sooner (Figure). Patients with CR's (55 of the 72 adults with responses lasting at least one year were CR's) had better long-term outcomes than did patients with PR's even more than one year from initial treatment. B-cells returned significantly sooner to higher levels in subjects who relapsed compared to those whose responses were ongoing. No clinical long-term toxicity was observed but 2 patients were identified to have mild hypogammaglobulinemia > 30 months from initial treatment. Conclusions: In summary, only approximately 1 in 5 adults treated with rituximab will have an at least five-year relapse-free response rate which is disappointingly low; children have only a slightly higher five-year relapse-free response rate. A pilot study to improve outcomes using either R-CVP or double dose rituximab was unsuccessful (Hasan, Am J Hematol,2009) Current efforts to improve long-term response rates have focused on the combination of high dose dexamethasone and rituximab (or even by providing maintenance treatment with rituximab). A better understanding of the mechanism of effect of rituximab in patients with ITP might allow an improved treatment strategy to be developed. Fortunately, the toxicity of rituximab treatment in patients with uncomplicated ITP appears to be low; however, yearly testing for immunoglobulins for a minimum of five years might be appropriate. Disclosures: Neufeld: Novartis. Inc: Research Funding. Shenoy:Novartis Oncology: Honoraria. Bussel:Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy.

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