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.

scholarly journals Long-Term Outcome of Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib Front-Line

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-45
Author(s):  
Franck E Nicolini ◽  
Vincent Alcazer ◽  
Pascale Cony-Makhoul ◽  
Stephanie Dulucq ◽  
Sandrine Hayette ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Front Line ◽  
Advisory Committees ◽  
Long Term Outcome

Nilotinib (NIL) 600 mg daily has demonstrated its superiority over Imatinib 400 mg daily in terms of response and incidence of deep molecular response in the front-line chronic phase (CP) CML setting. In this observational study we have retrospectively analyzed the outcome of in- and out-study 202 patients (pts) treated in this setting with NIL 600 mg front-line, in "real-life" conditions. All pts with newly diagnosed adult CP-CML receiving NIL 300 mg BID alone front-line between 10/2007 and 06/2020, were eligible for this study. Data were retrospectively collected according to the current French regulations with pts' information. All pts were assessed and followed according to ELN recommendations 2003, 2006, and 2009 along treatment and to the recommendations from the French group of CML (D. Rea et al., Cancer 2018) in case of TFR. In this regard, a TKI was resumed if loss of MMR. All BCR-ABL1 assessments were performed in the 3 reference laboratories, standardised and expressed in % (IS) with ≥32,000 copies of ABL1 as control. The primary endpoints were the rate of molecular responses in the long-term and the (vascular) safety of Nilotinib. Secondary endpoints were the kinetics of molecular response, survival and safety of Nilotinib. Survival (OS, PFS & EFS) was defined according to ELN (J. Guilhot et al. Blood 2012). Two hundred and two patients were reported with 44% females and 56% males with a median age at diagnosis of 50.4 (17.5-83) years, and 26% of them had cardiovascular risk factors at onset (tobacco abuse 11%, hypercholesterolemia 9.3%, diabetes 1.45%, none with past history of cardiovascular events [CVE]). ELTS scores were high in 14%, intermediate in 31% and low in 55% of pts. Twenty-four (12%) pts harboured additional chromosomal abnormalities at diagnosis. The median follow-up after NIL initiation was 61.5 (1-147.5) months. At last follow-up 113 pts (55%) are not on NIL anymore for toxicities, TFR or resistance reasons. Twenty-eight (14%) pts present an arterial event on NIL (18% PAOD, 14% angina pectoralis, 7% myocardial infarction, 14% stroke, 47% others such as atrial fibrillation, cardiomyopathy...), that occurred after a median of 26 (0.6-98.5) months on NIL. Forty-six (22.5%) pts reached TFR criteria and stopped NIL after a median of 58.5 (27-126) months. The cumulative incidence (CI) rates of MMR at 1, 2 and 5 years were 64 (57-71)%, 79.4 (75.45-83.35)% and 95 (92-98.5)% respectively. For MR4, those were 35.5 (29-42)%, 60 (52-67)% and 82 (74.5-89)% respectively; and for MR4.5, were 14 (9-19)%, 31 (24-28)% and 62 (54-70.5)% respectively. The CI of sustained MR4.5 (i. e. patients eligible for TFR: MR4.5 ≥2 years) was observed in 30 (23-37)% at 3 years, 45.5 (36-55)% at 5 years and 52.5 (41.5-64)% at 6 years (Figure). The CI of patients entering TFR was 16.75 (10.5-23)% at 5 years and 51.94 (37.31-66.57)% at 10 years with a survival without MMR loss of 70.7 (58- 86)% at 1 year and 65.26 (50.6-84)% at 5 years. Nine (4.5%) pts progressed towards accelerated phase (4 pts) or BC (2 lymphoid, 3 myeloid) responsible for 5 deaths at latest follow-up. Among NIL resistant patients screened, 15 were harbouring ABL1 mutations (5 Y253H, 3 E255K, 3 T315I, 1 M244V, 1 G250E, 1 F359V, 1 V299L). Overall, 10 patients died (5 from CML, 5 from unrelated causes). The probability of OS was 95.75 [95%CI: 92.9-98.7]% at 2 years and 94.8 [91.5-98.3]% at 5 years, for PFS it was 94.92 [91.7-98.2]% at 2 years and 89.5 [84.7-94.6]% at 5 years, and EFS it was 78 [72.3-84]% at 2 years and 60.25 [53.3-68.1]% at 5 years. Regarding sustained MR4.5, univariate analysis showed that female gender (HR=2.46 [1.50-4.02], p<0.001) and low ELTS (HR=0.41 [0.22-0.76], p<0.004) had a significant impact, while multivariate analysis confirmed the role of these 2 factors (HR=2.31 [1.41- 3.79], p=0.001 and HR= 0.52 [0.30- 0.90], p=0.02) in addition to high ELTS (HR= 0.28 [0.14- 0.58], p<0.001). Univariate and multivariate analyses demonstrated that only age impacted on the CI of CVE (HR= 1.07 [1.04-1.10], p<0.001, and HR=1.07 [1.04-1.10], p<0.001). NIL first-line efficiently limits progression of newly diagnosed CP-CML patients and provides high rates of sustained MR4.5, allowing TFR in a substantial proportion of pts. However, the onset of arterial occlusive events, especially in the elderly is a matter of concern in the choice of this compound at treatment initiation. Disclosures Nicolini: Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Sun Pharma Ltd: Consultancy. Cony-Makhoul:BMS: Speakers Bureau; Incyte Biosciences: Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy; BMS: Consultancy. Dulucq:Incyte: Speakers Bureau; Novartis: Speakers Bureau. Cayuela:Novartis: Speakers Bureau; Incyte: Speakers Bureau. Rea:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mahon:ARIAD: Honoraria; Pfizer: Honoraria; Novartis Pharma: Honoraria, Research Funding; BMS: Honoraria. Etienne:Pfizer: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau.

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.

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 Impact of Age on Efficacy, Safety, and Long-Term Outcome of Chronic Myeloid Leukemia (CML) Patients Treated in First-Line with Nilotinib: An Analysis of the Gimema CML Working Party

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3068-3068 ◽  
Author(s):  
Gabriele Gugliotta ◽  
Fausto Castagnetti ◽  
Massimo Breccia ◽  
Mariella D'Adda ◽  
Fabio Stagno ◽  
...  
Keyword(s):  
Research Funding ◽  
Age Groups ◽  
Molecular Response ◽  
Line Treatment ◽  
First Line ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Group A ◽  
Group B ◽  
First Line Treatment

Abstract Background: In chronic phase (CP) chronic myeloid leukemia (CML) the disease characteristics at diagnosis, risk distribution, probability of transformation to accelerated/blast phase (AP/BP), and toxicities may vary according to age. Nilotinib has shown better efficacy compared to imatinib, but it has been associated to a higher incidence of arterial thrombotic events (ATEs). Little is known on the efficacy, safety and long-term outcome of nilotinib treated patients in different age groups. Aims: To investigate the efficacy and safety, particularly the cardiovascular safety, of first-line treatment with nilotinib according to age distribution. Methods: We analyzed 345 patients ≥ 18 years of age with CP CML enrolled in clinical trials of the GIMEMA CML WP investigating nilotinib as first-line treatment. Patients were treated with: nilotinib 400 mg BID (n=73); rotation of nilotinib 400 mg BID / imatinib 400 mg OD (3-month periods for each drug)(n=123); nilotinib 300 mg BID (n=149). The median follow-up was 58 months. We divided the patients in 3 groups of age (table): 18-49 years (group A, 147 pts, median age: 39 years); 50-64 years (group B, 109 pts, median age 58 years); and ≥ 65 years (group C, 89 pts, median age 71 years). We analyzed in detail the response rates, events and outcome. Definitions: Major molecular response (MMR): BCR-ABL≤0.1% (IS), with > 10.000 ABL copies; MR4: BCR-ABL≤0.01% (IS), with > 10.000 ABL copies. Events: permanent discontinuation of nilotinib for any reason, including adverse events, progression to AP/BP, or deaths. ATEs: peripheral arterial obstructive disease (PAOD), acute coronary syndrome, chronic ischemic heart disease, significant carotid stenosis and ischemic stroke, or other significant ischemic events. Results: EUTOS high risk patients were: 8.8, 5.5, 1.1% in group A, B, and C, respectively (p=0.048). We did not observe significant differences in molecular response rates (table), including BCR-ABL/ABL <10% at 3 months, MMR and MR4 at 12 months, and cumulative incidences by 5 years of MR3 and MR4. Events leading to permanent nilotinib discontinuations occurred in 31%, 29%, and 42% of group A, B, and C, respectively (p=0.049). Overall, 29 ATEs were recorded, with higher rates, as expected, in elderly patients (group A: 2%; B: 11%; C: 15.7%; p=0.006); relative risk for ATEs in group B vs. A: 5; relative risk in group C vs. A: 6.7. ATEs were the reason for permanent nilotinib discontinuation in 2% of pts 18-49 years, 7.3% of pts 50-64 years, and 11.2% of pts > 65 years (p=0.015). Progressions to AP/BP were significantly more frequent in younger (18 - 49 years) patients (6.8%) compared to older (> 50 years) patients (1.5%), p= 0.019. Overall, 19 patients died (group A: 4.8%; B: 2.8%; C: 10%). In patients < 65 years all deaths (10) were leukemia-related, while in patients >65 years, all but one (8/9) deaths were leukemia-unrelated. The 6-year overall-survival was 94%, 97%, and 84% in pts 18-49 years, 50-64 years, and > 65 years of age (p=0.12) Summary/Conclusion: Nilotinib as first-line treatment of newly diagnosed CP CML patients showed high rates of molecular responses in all age groups. However, compared to older patients, significant more progressions occurred in younger (18-49 years) ones; the causes of death in this group were all leukemia-related. In contrast, in elderly patients (>65 years) the causes of death were almost all leukemia-unrelated. ATEs were rare (2%) in patients of 18-49 years, while high rates (> 10%) of ATEs were recorded in those of 50-64 years; as expected, ATEs occurred even more frequently in patients > 65 years. These data suggest that while in patients > 50 years more attention should be focused on the prevention of ATEs, in younger ones more efforts are needed to avoid the progression of CML to accelerated/blast phase. Disclosures Gugliotta: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Castagnetti:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; ARIAD Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Breccia:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Soverini:Ariad: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Cavo:Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Martinelli:Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy; Roche: Consultancy; MSD: Consultancy; Novartis: Speakers Bureau; Amgen: Consultancy; Genentech: Consultancy; BMS: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy; Roche: Consultancy; MSD: Consultancy; Amgen: Consultancy; Genentech: Consultancy. Saglio:Ariad: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy. Baccarani:Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Other: personal fees, Speakers Bureau; Ariad: Honoraria, Other: personal fees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Rosti:Roche: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

Long Term Outcome of Patients with Acute Promyelocytic Leukemia Treated with All-Trans Retinoic Acid, Arsenic Trioxide with or without Gemtuzumab Ozogamicin

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3776-3776
Author(s):  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
Guillermo Garcia-Manero ◽  
Elihu Estey ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Gemtuzumab Ozogamicin ◽  
Low Risk ◽  
Newly Diagnosed ◽  
Term Outcome ◽  
Long Term Outcome ◽  
High Risk Patients ◽  
Risk Patients

Abstract Background - Combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) for the initial treatment of patients with low and intermediate risk acute promyelocytic leukemia (APL) has been shown to be superior to ATRA plus chemotherapy but there is limited available long-term follow up on the "chemotherapy-free" combinations. Methods - We examined the long-term outcome of patients with newly diagnosed APL treated at our institution on three consecutive prospective clinical trials of the combination of ATRA and ATO with or without gemtuzumab ozogamicin (GO) (ID01-014; NCT01409161; NCT00413166). Initially patients received ATRA 45 mg/m2 in two divided doses daily and beginning 10 days later, ATO 0.15 mg/kg daily. With subsequent studies, the schedule was modified for all patients to receive concomitant therapy with ATRA and ATO from day 1. Patients with WBC > 10 x 109/L and patients whose WBC rose to greater than 10 x 109/L during therapy also received a dose of GO 9 mg/m2. Standard supportive care as well as steroids for prophylaxis for differentiation syndrome were administered to all patients. A bone marrow exam to assess response was performed between days 21 and 28 and, if necessary, repeated weekly. Once in CR, patients received consolidation with ATO 0.15 mg/kg daily 5 days/week for 4 weeks every 8 weeks for a total of 4 cycles and ATRA 45 mg/m2 daily for 2 weeks every 4 weeks for a total of 8 months. Bone marrow assessment was performed every 3 months for 1 year and if PCR for PML-RARA was confirmed positive, a dose of GO would be administered. Results - From July 2002 to May 2015, 183 patients have been enrolled into the three trials. During the same period a total of 235 patients with newly diagnosed APL were seen at our institution. Reasons for not being enrolled in the studies were: insurance/socio-economic in 39 (75%) and died within 48 hours of presentation in 13 (25%). Median age of the study patients was 50 years (range, 14-84). 52 (28%) were older than 60 years. Median WBC at presentation was 2.2 x 109/L (range, 0.3-187.9). 52 (28%) had high risk disease with WBC > 10 x 109/L and 131 (72%) had low risk disease with a WBC ≤ 10 x 109/L. Cytogenetics were t(15;17) alone in 117 (64%), t(15;17) plus other in 48 (26%), other, not done, or insufficient in 18 (10%). PCR was positive for PML-RARA in all patients (100%) with the long isoform in 104 (57%), short in 78 (43%), and both in 1 (<1%). Overall 176 (96%) achieved CR with CR rate of 96% for low risk patients and 96% for high risk patients. Early death (occurring within 1 month of study entry) occurred in 7 (4%) and was due to 1 infection/multi-organ failure (MOF), 3 hemorrhage, 3 MOF/hemorrhage/infection. Differentiation syndrome was diagnosed in 21 (11.5%) Other toxicities included QT prolongation in 14 (7.7%), infections in 44 (24.0%), and hemorrhagic events in 10 (5.5%). The median duration of follow-up is 39.6 months (range, 0.8 - 138.8). Six patients (3%) have relapsed including 2 (1%) with extramedullary (both CNS) relapse. The median event-free (EFS), disease-free (DFS) and overall survival (OS) have not yet been reached. The 5-year EFS is 85%, DFS is 96%, and OS is 87% (Figures 1). The 5-year DFS and OS for low risk patients is 99% and 88%, respectively and for the high risk patients 87% and 85%, respectively (figure 2). Conclusion - The combination of ATRA and ATO, with and without GO is effective and associated with excellent long-term DFS and OS in both low and high risk patients with newly diagnosed APL. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Cortes: Teva: Research Funding; BerGenBio AS: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Jabbour:Pfizer: Consultancy, Research Funding. Faderl:Celator: Research Funding; Astellas: Research Funding; Seattle Genetics, Inc.: Research Funding; Karyopharm: Consultancy, Research Funding; Onyx: Speakers Bureau; Ambit: Research Funding; BMS: Research Funding; JW Pharma: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding. Wierda:Glaxo-Smith-Kline Inc.: Research Funding; Celgene Corp.: Consultancy. DiNardo:Novartis: Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: 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.

scholarly journals LGG-06. LONG-TERM OUTCOME OF NEWLY DIAGNOSED LOW GRADE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii367-iii367
Author(s):  
Nongnuch Sirachainan ◽  
Attaporn Boongerd ◽  
Samart Pakakasama ◽  
Usanarat Anurathapan ◽  
Ake Hansasuta ◽  
...  
Keyword(s):  
Surgical Management ◽  
Progression Free Survival ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Newly Diagnosed ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Common Location ◽  
Suprasellar Region

Abstract INTRODUCTION Low grade glioma (LGG) is the most common central nervous system (CNS) tumor in children accounted for 30–50%. Regarding benign characteristic of disease, surgical management remains the mainstay of treatment. However, surgical approach is limited in some conditions such as location at brainstem or infiltrative tumor. Chemotherapy and radiation treatments have been included in order to control tumor progression. The 5-years survival rate is approach 90% especially in patients who receive complete resection. However, the outcome of children with LGG in low to middle income is limited. Therefore, the aim of the study was to determine long-term outcome of children with newly diagnosed LGG. METHODS A retrospective study enrolled children aged &lt;18 years who were newly diagnosed LGG during January 2006- December 2019. Diagnosis of LGG was confirmed by histological findings of grade I and II according to WHO criteria. RESULTS A total of 40 patients, female to male ratio was 1:1.35 and mean (SD) for age was 6.7 (4.0) years. The most common location was optic chiasmatic pathway (42.5%), followed by suprasellar region (25.0%). Sixty percent of patients received at least partial tumor removal. Chemotherapy and radiation had been used in 70% and 10.0% respectively. The 10-year progression free survival was 74.1±11.4% and overall survival was 96.2±3.8%. SUMMARY: Treatment of Pediatric LGG mainly required surgical management, however, chemotherapy and radiation had been used in progressive disease. The outcome was excellent.

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