Response to Frontline Therapy with Second Generation Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: Analysis of Outcome for b3a2 Vs. b2a2 Fusion Transcripts

Abstract Abstract 3781 Background: CML is characterized by the reciprocal translocation between chromosomes 9 and 22 [t(9;22)(q34;q11.2)], also known as the Philadelphia chromosome. This results in the formation of the BCR-ABL fusion gene, which is translated to a protein with increased tyrosine kinase activity. The breakpoint in the BCR gene can occur in different sites, most commonly between exons 13 and 15 which fuse to exon 2 of the ABL gene creating the b2a2 and b3a2 junctions. Previous studies have reported a better outcome for patients (pts) having a b2a2 transcript when treated with imatinib. To our knowledge there are no published reports analyzing the outcome of pts treated with a 2ndgeneration TKI as initial therapy for CML according to the fusion transcript. We analyzed the significance of these variations among pts with CML in chronic phase (CP) enrolled in 2 parallel trials of dasatinib and nilotinib as initial therapy. Patients and Methods: A total of 204 pts with CML in CP, treated at our institution between 2005 and 2012 with nilotinib or dasatinib as frontline therapy were included in this analysis. Among them 88 (43%) had the b2a2 transcript (median age of 47 years; range 18–80) at the start of therapy, 74 (36%) showed the b3a2 variant (median age of 47; range 17–82 years), and 42 (21%) presented both (median age 53; range 27–81). One patient had a b3a3 transcript and 2 pts showed an e1a2 transcript. Forty-two (48%) of those with b2a2 were treated with dasatinib and 46 (52%) with nilotinib; of the pts with b3a2 34 (46%) were treated with dasatinib and 40 (54%) with nilotinib, in the group of pts with both transcripts 24 (57%) received dasatinib 24, and 18 (43%) of them nilotinib (Table 1). Results: The Sokal risk group for those with the b2a2 transcript was high in 10%, intermediate in 29%, and low in 61%. For pts with b3a2 the risk classification was 5%, 25, and 70%, respectively. The group with both transcripts had 10%, 31% and 69%, respectively. Significant difference was observed in the time of molecular response and overall outcome between pts with b2a2 and those with b3a2 (CCyR 91% vs. 96%; MMR 75% vs. 91%, respectively). The 3-year probability of overall survival (OS) was 100% for both groups. The 3-year probability of event-free survival (EFS) was 93% and 99%, and the transformation-free survival (TFS) 99% and 98% for the b2a2 and the b3a2 group respectively (Table 2). On the 12 mo. follow-up one of the pts with e1a2 transcript achieved CCyR (treated with nilotinib), and the second patient (pt) major cytogenetic response (receiving dasatinib). The pt presenting with b3a3 was treated with dasatinib and achieved MMR by 3 mo. and CCyR at the 12 months follow-up. Conclusions: Although all pts whether they express b3a2 or b2a2 at diagnosis, have an excellent overall survival, those with b3a2 have a significantly higher rate of molecular responses and a trend for better EFS. These results mirror what we have previously reported for pts treated with imatinib as initial therapy. The biologic characteristics for this difference warrant further investigation. Disclosures: Kantarjian: Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Ariad: Research Funding; Pfizer: Research Funding. Jabbour:Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Cortes:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

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

Blood ◽

10.1182/blood.v126.23.2796.2796 ◽

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.

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Prognostic Implication of Early Molecular Response at 3 Months in Chronic Myeloid Leukemia Patients: A Comparison of Imatinib and Second Generation Tyrosine Kinase Inhibitors

Blood ◽

10.1182/blood-2018-99-117631 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3017-3017

Author(s):

Dong-Wook Kim ◽

Sung-Eun Lee ◽

Soo Young Choi ◽

Dae Young Zang ◽

Won-Sik Lee ◽

...

Keyword(s):

Tyrosine Kinase ◽

Research Funding ◽

Kinase Inhibitors ◽

Molecular Response ◽

Long Term Outcomes ◽

Free Survival ◽

Frontline Therapy ◽

The Impact

Abstract Background: Although several studies have demonstrated that BCR-ABL1 transcript levels at 3 months were prognostically significant in patients treated with frontline imatinib (IM) and second-generation tyrosine kinase inhibitors (2G-TKIs), the decision to change treatment based on early molecular response (EMR) status remain under investigaiton. Because CML patients currently have multiple treatment options, the impact of early molecular milestones on long-term outcomes needs to be determined in each agent treated patients. Aims: The aim of this study is to evaluate the impact of 3-month early molecular response (EMR) on long-term outcomes of CML patients treated with IM and different 2G-TKIs, as additional information to guide clinical decisions on switching to a different TKI. Methods: 734 new CP CML patients who were treated with frontline IM (n = 366) or 2G TKIs (n = 368) were analyzed. Molecular responses were monitored using qRT-PCR assay in 3 month intervals by achieving major molecular response (MMR), and then 6 month intervals after achieving MMR. Main study objectives were to evaluate the long-term outcomes, including failure-free survival (FFS), progression-free survival (PFS), and overall survival (OS), according to 3-month EMR. FFS was measured from the date of treatment start until death, progression to AP or BP, or ELN failure on treatment, whichever came first. PFS and OS collected survivals on patients who were treated with other TKIs after frontline therapy discontinuation. Results: A total of 734 patients were treated with imatinib (IM; n = 366), dasatinib (DAS; n = 141), nilotinib (NIL; n = 89), and radotinib (RAD; n = 138). The median age was 43 years (range, 11-87). The percentages of patients with low, intermediate, and high Sokal risk scores were 37%, 38% and 23%, respectively, with 2% unknown risk. With a median follow-up of 85.6 (IM; range, 4.4-207.5) and 38.9 (2G-TKIs; range, 11.6-130.2) months, 460 (62.7%; 182 IM and 218 2G-TKIs) patients continue on the frontline therapy and 274 (37.3%) patients were permanently discontinued or changed to other TKIs due to intolerance (73 IM, 38 DAS, 2 NIL, 28 RAD), ELN failure (32 IM, 3 DAS, 2 NIL, 3 RAD), progression (3 IM, 1 DAS, 1 RAD), and others (60 warning, 3 pregnancy, 14 treatment-free remission study, and 9 follow-up loss). In 366 patients treated with IM, patients achieving BCR-ABL1 ≤ 10% at 3 months (n = 275, 75.1%) had a better outcomes in terms of 8-y OS (97.4% vs 89.7%, P <0.001), 8-y PFS (96.3% vs 88.6, P=0.002), and 8-y FFS (91.5% vs 74.6%, P<0.001) compared with those of the patients with BCR-ABL1 >10%. In 368 patients treated with 2G-TKIs, achievement of 3-month EMR (n = 331, 90.0%) was associated with a higher 8-y OS (98.6% vs 91.9%, P <0.001), 8-y PFS (98.2% vs 91.7, P=0.001), and 8-y FFS (96.5% vs 82.7%, P<0.001). The prognostic impact of 3-month EMR was observed in both IM and 2G-TKIs treated groups. Conclusions: Our data showed that EMR failure at 3 months could translate into poor survival outcomes in patients treated with frontline IM and 2G-TKIs.However, to confirm the benefit of an early switch of therapy, further investigations in a larger patient population with longer follow-up are needed. Disclosures Kim: Pfizer: Research Funding; BMS: Research Funding; Novartis: Research Funding; Ilyang: Research Funding.

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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 ◽

10.1182/blood.v116.21.3438.3438 ◽

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

Blood ◽

10.1182/blood.v118.21.4443.4443 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4443-4443

Author(s):

Mahran Shoukier ◽

Hagop M. Kantarjian ◽

Elias Jabbour ◽

Alfonso Quintas-Cardama ◽

Zeev Estrov ◽

...

Keyword(s):

Risk Factors ◽

Tyrosine Kinase ◽

Research Funding ◽

Chronic Phase ◽

Initial Therapy ◽

Myelogenous Leukemia ◽

Molecular Response ◽

Close Monitoring ◽

Pancreatic Cell ◽

Free Survival

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

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The Outcome of Patients (pts) with Chronic Myeloid Leukemia (CML) Treated with Imatinib Outside of a Clinical Trial or On a Clinical Trial At a Single Institution

Blood ◽

10.1182/blood.v120.21.1693.1693 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1693-1693

Author(s):

Musa Yilmaz ◽

Hagop M. Kantarjian ◽

Elias J. Jabbour ◽

Susan M. O'Brien ◽

Gautam Borthakur ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Research Funding ◽

Cytogenetic Response ◽

Molecular Response ◽

Single Institution ◽

Free Survival ◽

Excellent Outcome ◽

Significant Difference

Abstract Abstract 1693 Background: Outcomes of CML chronic phase (CP) pts treated in clinical trials are frequently perceived to not be representative of those treated outside of clinical trials (Lucas et al, Haematologica 2009; 94: 1362–7). The latter is frequently referred to as “the real world” world experience. Some reports have suggested that outcome of pts treated outside of clinical trials have an inferior outcome. We investigated the outcomes of pts receiving imatinib on and off a clinical trial for CML-CP at a single institution. Methods: We reviewed the medical records of all pts with CML-CP treated at MDACC between 2000 and 2012 to identify pts that received initial therapy with imatinib 400 mg on a clinical trial or as standard therapy outside of a clinical trial (“off protocol” group). Only pts who had not received any prior therapy, or only hydroxyurea, or interferon alpha for less than 1 month, and that initiated on 400 milligram daily dose of imatinib within 6 months of diagnosis were included. Event-free survival (EFS) was measured from the start of treatment to the date of any of the following events: loss of major cytogenetic response (MCyR), loss of complete hematologic response (CHR), transformation to accelerated phase (AP) and blast phase (BP), and death while on imatinib. Transformation-free survival (TFS) was measured from the start of treatment to the date progression to AP/BP during therapy, last follow-up, or death from any cause. Overall survival (OS) was measured until death form any cause at any time. Results: We identified 65 pts treated with imatinib off protocol during the period of interest. During this time 71 pts were treated on clinical trials with imatinib. The median age was 49 yrs (15–79) for pts on clinical trials and 49 yrs (15–84) for those off protocol, respectively. The median follow-up was 125 months (13 to 142) for pts on clinical trials and 51 months (2 to 117) for those off protocol. The overall complete cytogenetic response (CCyR) rates were 84% and 83% for patients treated on and off protocol, respectively. CCyR rates, 12 months after initiation of imatinib, were not different (60% vs 66%, respectively; p=.15). Pts treated on protocol had higher rates of major molecular response (MMR) (79% vs 58%, P=.012) and complete molecular response (CMR = undetectable with sensitivity of at least 4 logs) (42% vs 32%, P=.045) at any time compared to the pts treated off protocol. This is likely due to the longer follow-up for pts on protocol as MMR takes longer to occur. In fact, the MMR rate at 12 months were 30% and 24% in pts treated on and off protocol, respectively (p=.28). Analyzing earlier responses, 3-month rates of MCyR were 71% on protocol and 69% off protocol (p=.82). Corresponding rates at 6 months were 82% and 85%, respectively (p=.68). The 5-year EFS rates were 86% and 84% for on and off protocol patients, respectively. There was also no significant difference in 5-year TFS (96% vs 94%) and OS (90% vs 96%). Conclusion: These results suggest that pts with CML treated outside of a clinical trial may have the same excellent outcome as those treated on a clinical trial provided they are followed with the same rigor. Disclosures: Ravandi: BMS: Research Funding. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

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Interim or End of Treatment FGD-PET Complete Response Does Not Have Adequate Predictive Value in Mature T/NK Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.1813.1813 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1813-1813

Author(s):

Tatyana Feldman ◽

Larysa Sanchez ◽

Patrick Toth ◽

David Panush ◽

Lori A Leslie ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Predictive Value ◽

Research Funding ◽

Nk Cell ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Significant Difference

Abstract Introduction: Cure rate of Mature T/NK cell lymphoma (TCL) is rather low and multiple trials are being conducted to improve frontline therapy outcomes. Consolidation with autologous stem cell transplant is becoming widely used as a mean of improving survival (SCT). Based on data from several retrospective trials, pts who achieve CR may not benefit from consolidative SCT. There is no data available on the role of PET-CR as defined by using Deauville criteria (which became standard in response assessment of NHL (The Lugano Classification 2014)). We performed retrospective analysis of 59 pts with TCL examining the correlation between PFS/OS and iPET and eotPET. Methods: 59 pts newly diagnosed pts with TCL treated between 2008-2016 for whom interim and eotPET scan were available. It was our routine practice to obtain baseline, interim (after 3 cycles of chemotherapy) and eotPET. Pathology slides of outside cases were centrally evaluated by a hematopathologist to confirm diagnosis. Baseline, interim and eotPET were centrally reviewed by a nuclear medicine radiologist blinded to clinical outcomes who assigned Deauville score (DS) to every PET. Responses were recorded according to the Lugano classification 2014. Descriptive statistics and Kaplan Meier method was used to calculate the Progression-free survival (PFS) and Overall survival (OS), two-sided Log-rank test was used to compare OS and PFS between PET groups. Results: Detailed demographic is presented in Table1. Median age at diagnosis is 59, sixty two percent males, 37% female; ALCL 34%, PTCLnos 22%, AITL 19%, and ATLL 10%; most of pts were advanced stage. Most common chemotherapy regimens used were CHOP/CHOEP, HCVAD, and CODOX, SMILE. Median follow up time for the entire cohort was 22.7mo. Forty nine percent of pts progressed and 29% of pts died during follow up. Cause of death for majority of pts was disease progression. Following Deauville scores were assigned on iPET and eotPET respectively: DS1 in 37% and 39%, DS2 in 30% and 35%, DS3 in 15% and 6%, DS4 in 9% and 4%, DS5 in 9% and 16%. We analyzed mPFS and mOS for PET-CR using DS1-2 or DS1-3 to define it. Sixty seven percent and 82% were considered in PET-CR on iPET based on DS 1-2 and DS 1-3 respectively. PET-CR went up to 77% and 83% respectively on eotPET. For final analysis, DS1-2 was used to define PET-CR as no statistically significant difference in mPFS and mOS was noted between DS1-2 and DS1-3. With median follow up of 22.7mo, two-year mPFS and mOS for the cohort were 50% and 74% respectively. Two- year mPFS for iPET-CR and eotPET-CR were 62%. Two-year mOS for iPET-CR and eotPET-CR were 86%% and 83%. Two-year mPFS for iPET-PR and eotPET-PR were 37% and 67%. Two-year mOS for iPET-PR and eotPET-PR were 70% and 100 % (not statistically significant difference with PET-CR mPFS and mOS). None of the pts with PD on iPET were alive at two year. Two-year mOS for eotPET-SD and eotPET-PD are 40%. Negative predictive value of iPET and eotPET is 61%, positive predictive value is 65% and 72% respectively. Conclusion: While PET-SD and PD is quite predictive of poor survivorship, significant number of PET-CR pts will relapse. Even though PET-CR rate to frontline therapy is high, it does not translate into durable responses for significant number of pts with TCL. Thus, PET-CR is not a sensitive enough measure to be considered as a predictor of long-term remission in TCL. It is important to develop response assessment tools which will correlate better with long term survivorship of TCL patients. Figure 1 Overall survival stratified on PET response Figure 1. Overall survival stratified on PET response Figure 2 Progression free survival stratified on PET response Figure 2. Progression free survival stratified on PET response Disclosures Feldman: Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Skarbnik:Pharmacyclics: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Mato:Theradex: Research Funding; TG Therapeutics: Research Funding; ProNAi: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma: Research Funding; Abbvie: Research Funding; TG Therapeutics: Consultancy; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy; Abbvie: Consultancy. Chow:Seattle Genetics: Speakers Bureau. Protomastro:COTA: Employment. Leslie:Celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau. Goy:Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Frontline Tyrosine Kinase Inhibitors (TKI) As Initial Therapy for Patients with Chronic Myeloid Leukemia in Accelerated Phase (CML-AP),

Blood ◽

10.1182/blood.v118.21.3779.3779 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3779-3779

Author(s):

Maro Ohanian ◽

Hagop M. Kantarjian ◽

Alfonso Quintas-Cardama ◽

Susan O'Brien ◽

Srdan Verstovsek ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Research Funding ◽

Clonal Evolution ◽

Cytogenetic Response ◽

Initial Therapy ◽

Molecular Responses ◽

Free Survival

Abstract Abstract 3779 Background: Some patients (pts) with chronic myeloid leukemia (CML) present with features of accelerated phase (AP) at the time of diagnosis. Imatinib, dasatinib, and nilotinib are standard initial tyrosine kinase inhibitor (TKI) therapy for pts with CML in chronic phase (CP). For pts with accelerated phase CML (CML-AP), data is available mostly on treatment after failing previous therapies, and there is no available data on nilotinib and dasatinib as initial therapy for CML-AP. Aim: To describe efficacy of imatinib, dasatinib, and nilotinib as initial therapy for patients with CML-AP. Methods: Frontline TKI therapy was administered on consecutive or parallel clinical trials to 58 CML pts who presented with features of AP at the time of diagnosis, defined as blasts ≥15% (n=8), basophils ≥20%, (n=22), platelets <100×109/L (n=3), cytogenetic clonal evolution (n=22), or more than 1 feature (n=3). 36 pts received imatinib. 22 pts received a second generation TKI (2GTKI) (desatinib, n = 5 or nilotinib, n= 17). Results: A total of 58 pts were treated. Median age was 46 years (range 22 to 81). Pt characteristics were similar in all 4 treatment groups. With a median follow-up of 32 months (range 2 to 125), a complete hematologic response (CHR) was achieved in 93%, a partial cytogenetic response (PCyR) in 2 %, and a complete cytogenetic response (CCyR) in 82%. The rate of CCyR for evaluable patients treated with imatinib was 75%, and with 2GTKIs, 95%. Major molecular responses (MMR, BCR-ABL/ABL ≤0.1% IS) were achieved in 68% including complete molecular responses (CMR, BCR-ABL/ABL ≤0.0032% IS) in 49%. MMR rates for pts treated with imatinib were 66%, and with 2GTKIs, 71%. The median time to achieve a CCyR was 3 months, and a MMR, 9 months. The 12-month rate of CCyR was 74% with imatinib and 83% with 2GTKIs. The 12-month MMR rate was 52% for imatinib and 67% for 2GTKIs. Patients with clonal evolution as the only criterion for CML-AP had a 91% rate of CCyR compared to 76 % for those with other criteria (p=0.168). At 24 months from the start of therapy, event free survival (EFS) for all patients was 90% (imatinib 90%; 2GTKI 90%). 24-month transformation free survival (TFS) (survival free from transformation to blast phase) was 92% (imatinib 94%, 2GTKIs 90%). Overall survival at 24 months was 100% with both imatinib and 2GTKI's. We also analyzed the impact of early response on long-term outcome. The TFS rate at 24 months for those achieving a 12-month CCyR was 100% compared to 56% for those not achieving such responses. TFS was 100% for those with a MMR at 18 months and 60% for those without a MMR at 18 months. In total, 4 patients have transformed to BP. None of the patients who transformed had achieved CCyR by 12 months. At last follow-up, 34 patients remain on therapy. Reasons for discontinuation were treatment failure/disease progression in 8, toxicity in 1, and other reasons in 15. Conclusion: Patients with CML who present with features of AP at the time of diagnosis have an excellent outcome with TKIs, particularly 2GTKI. Those with clonal evolution as the only manifestation of AP have a particularly favorable outcome. TKIs should be considered standard initial therapy for patients with AP at the time of diagnosis. Disclosures: Kantarjian: Novartis: Consultancy; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding. Quintas-Cardama:Novartis: Consultancy; BMS: Consultancy. Ravandi:BMS: Honoraria; BMS: Honoraria; Bristol Meyers-Squibb: Research Funding. Jabbour:Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

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Outcomes of Patients with Relapsed or Refractory Acute Myeloid Leukemia Receiving Hypomethylating Agent and Venetoclax

Blood ◽

10.1182/blood-2019-128958 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1357-1357 ◽

Cited By ~ 2

Author(s):

Hannah Asghari ◽

Dasom Lee ◽

Yehuda E. Deutsch ◽

Onyee Chan ◽

Najla Al Ali ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Risk Groups ◽

Initial Therapy ◽

Intermediate Risk ◽

Advisory Committees ◽

Significant Difference ◽

Frontline Therapy ◽

Refractory Aml

Background: Patients with acute myeloid leukemia (AML) have dismal overall outcomes and survival is exceptionally poor in patients who experience relapse or are refractory (R/R) to frontline therapy. Since December 2018, combination therapy with hypomethylating agents (HMA) and venetoclax (HMA+Ven) has become standard frontline therapy for older patients or younger unfit patients. Moreover, it has been routinely utilized in patients experiencing relapsed or refractory AML yet response and outcome data is limited in patients with R/R disease. Thus, we investigated outcomes after HMA+Ven in patients with relapsed or refractory AML. Methods: We retrospectively annotated 72 patients who received treatment with HMA+Ven at Moffitt Cancer Center and Memorial Healthcare System between 2017 and 2019. Patients were divided into two subgroups: 1) initial remission therapy and 2) salvage therapy. Clinical and molecular data were abstracted in accordance with the Institutional Review Board approved protocol. Overall response rate (ORR) included patients achieving complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Patients achieving CR, CRi, or MLFS were termed as responders (RES) and patients without CR, CRi, or MLFS were nonresponders (NRES). Fisher's Exact method was used to determine significance for categorical variables. Kaplan-Meier analysis was performed to determine median overall survival (mOS) and log-rank test was utilized to determine significance. All p-values are two-sided. Results: Out of 72 patients, 41 received HMA+Ven as initial therapy and 31 received it in the R/R setting. Baseline characteristics are outlined in Table 1. Median age was 63 years for patients with R/R AML with 58% female. In the R/R cohort, ORR was 34.5% with 0 (0%) patients achieving CR, 8 (27.6%) patients achieving CRi, and 2 (6.9%) achieving MLFS (Table 2). When compared to patients receiving HMA+Ven as initial therapy, ORR was significantly lower in the R/R cohort (64.1% vs. 34.5%, p=0.03). Among 31 patients in the R/R cohort, 6.5% (n=2) proceeded to allogeneic stem cell transplant (allo-SCT) after achieving CRi. European LeukemiaNet (ELN) risk stratification was known in 22 patients in the R/R cohort and ORR were similar in patients in the favorable/intermediate risk group (n=8) compared to adverse risk group (n=14) (37.5% vs. 28.6%, p=1.0). When compared to HMA+Ven used as initial therapy, ORR among the R/R cohort were not different among adverse risk groups (58.3% vs. 28.6%, p=0.10); however, ORR were significantly lower among patients with favorable/intermediate risk (100% vs. 37.5%, p=0.009). At a median follow-up of 7.6 months (mo), mOS was 4.9mo in the R/R cohort with mOS among RES superior to NRES (not reached vs. 2.4mo, p=0.0009) (Figure 1). Moreover, mOS was inferior in R/R patients compared to initial therapy (4.9mo vs. 13.8mo, p=0.0013) (Figure 2). A total of 15 (48.4%) patients had HMA exposure prior to receiving HMA+Ven without apparent impact on mOS (3.7mo (prior HMA) vs. 4.9mo (no prior HMA), p=0.97). The median duration of CR/CRi was 5.2mo and the median time to CR/CRi was 2.4mo. Based on ELN risk groups, mOS was not statistically different among patients with favorable/intermediate risk disease compared to adverse risk disease (8.6mo (fav/int) vs. 2.8mo (adverse), p=0.07). Responses were also analyzed based upon somatic mutations (Figure 2). In patients with isocitrate dehydrogenase 1 and 2 mutations (IDH1/IDH2) compared to patients without IDH1/2, ORR were 60% vs. 25%, respectively (p=0.28) with no significant difference in mOS (7.2mo (IDHmut) vs. 3.1mo (IDHwt), p=0.38). Comparing patients with TP53 mutation to those without TP53 mutations, no significant difference in ORR (25% vs. 33%, p=1.0) or mOS (4.4mo vs. 6.9mo, p=0.0.84) was noted. Conclusion: Although combination therapy with HMA+Ven has yielded impressive responses as frontline therapy, response rates with this combination in the salvage setting are less encouraging with the possible exception of those patients with IDH1/IDH2 mutations. Nevertheless, responders to salvage HMA+Ven had a significant survival benefit compared to nonresponders, suggesting that this combination is a reasonable salvage option in patients with relapsed or refractory AML. Disclosures Padron: Incyte: Research Funding. Kuykendall:Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria; Janssen: Consultancy; Abbvie: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:JAZZ: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy. Talati:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria. OffLabel Disclosure: Venetoclax is approved in combination with hypomethylating agents (azacitidine or decitabine) or low dose cytarabine for treatment of newly diagnosed AML in adults aged 75 years or older, or those who have comorbidities that preclude the use of induction chemotherapy.

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ENESTnd Update: Continued Superiority of Nilotinib Versus Imatinib In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP)

Blood ◽

10.1182/blood.v116.21.207.207 ◽

2010 ◽

Vol 116 (21) ◽

pp. 207-207 ◽

Cited By ~ 18

Author(s):

Timothy P. Hughes ◽

Andreas Hochhaus ◽

Giuseppe Saglio ◽

Dong-Wook Kim ◽

Saengsuree Jootar ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Clonal Evolution ◽

Molecular Response ◽

Newly Diagnosed ◽

Advisory Committees ◽

Free Survival ◽

Superior Efficacy ◽

Rate Of Progression

Abstract Abstract 207 Background: Results from the phase 3, international, randomized ENESTnd trial have demonstrated the superior efficacy of nilotinib over imatinib with significantly higher rates of major molecular response (MMR), complete cytogenetic response (CCyR), and with significantly lower rates of progression to AP/BC on treatment. Here, we present data with a median follow-up of 18 months. Methods: 846 CML-CP patients were randomized to nilotinib 300 mg twice daily (bid) (n=282), nilotinib 400 mg bid (n=281), and imatinib 400 mg once daily (n=283). Primary endpoint was MMR (≤ 0.1% BCR-ABLIS) rate “at” 12 months, as previously presented. Key secondary endpoint was durable MMR at 24 months. Other endpoints assessed at 24 months include progression to AP/BC (with and without clonal evolution), event-free survival, progression-free survival, and overall survival (OS). Results: With a median follow-up of 18 months, the overall best MMR rate was superior for nilotinib 300 mg bid (66%, P < .0001) and nilotinib 400 mg bid (62%, P < .0001) compared with imatinib (40%). Superior rates of MMR were observed in both nilotinib arms compared with the imatinib arm across all Sokal risk groups (Table). The overall best rate of BCR-ABLIS ≤ 0.0032% (equivalent to complete molecular response, CMR) was superior for nilotinib 300 mg bid (21%, P < .0001) and nilotinib 400 mg bid (17%, P < .0001) compared with imatinib (6%). The overall best CCyR rate was superior for nilotinib 300 mg bid (85%, P < .001) and nilotinib 400 mg bid (82%, P=.017) compared with imatinib (74%). The superior efficacy of nilotinib was further demonstrated using the 2009 European LeukemiaNet (ELN) 12-month milestone in which fewer patients had suboptimal response or treatment failure on nilotinib 300 mg bid (2%, 3%) and nilotinib 400 mg bid (2%, 2%) vs imatinib (11%, 8%). Rates of progression to AP/BC on treatment were significantly lower for nilotinib 300 mg bid (0.7%, P=.006) and nilotinib 400 mg bid (0.4%, P=.003) compared with imatinib (4.2%). The rate of progression on treatment was also significantly lower for nilotinib when including clonal evolution as a criteria for progression (Table). There were fewer CML-related deaths on nilotinib 300 mg bid (n=2), and 400 mg bid (n=1) vs imatinib (n=8). Estimated OS rate (including data from follow-up after discontinuation) at 18 months was higher for nilotinib 300 mg bid (98.5%, P=.28) and nilotinib 400 mg bid (99.3%, P=.03) vs imatinib (96.9%). Both drugs were well-tolerated. Discontinuations due to adverse events or laboratory abnormalities were lowest for nilotinib 300 mg bid (7%) compared with nilotinib 400 mg bid (12%) and imatinib (9%). With longer follow up there has been minimal change in the occurrence of AEs. Minimum 24-month follow-up data for all patients will be presented. Conclusions: With longer follow-up, nilotinib was associated with a significantly lower rate of progression to AP/BC on treatment and lower rates of suboptimal response or treatment failure vs imatinib. Nilotinib resulted in fewer CML-related deaths and a higher OS rate vs imatinib. Nilotinib induced superior rates of MMR, CMR, and CCyR vs imatinib in patients with newly diagnosed CML-CP. Taken together, these data support nilotinib as a new standard of care for patients with newly diagnosed CML. Disclosures: Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Meyers Squibb: Honoraria, Research Funding; Ariad: Honoraria. Hochhaus:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. le Coutre:Novartis: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Reiffers:Novartis: Research Funding. Pasquini:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Clark:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Honoraria, Research Funding. Gallagher:Novartis Pharma AG: Employment, Equity Ownership. Hoenekopp:Novartis Pharma AG: Employment. Haque:Novartis: Employment. Larson:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

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Outcome After Failure to Second Generation Thyrosine Kinase Inhibitors(TKI) Treatment as Frontline Therapy for Patients with Chronic Myeloid Leukemia (CML) In Chronic Phase(CP).

Blood ◽

10.1182/blood.v116.21.3442.3442 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3442-3442

Author(s):

Alireza Eghtedar ◽

Hagop Kantarjian ◽

Elias Jabbour ◽

Susan O'Brien ◽

Alfonso Quintas-Cardama ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Stem Cell Transplant ◽

Cytogenetic Response ◽

Initial Therapy ◽

Subsequent Treatment ◽

Cell Transplant ◽

2Nd Generation ◽

Frontline Therapy

Abstract Abstract 3442 Background: Imatinib has been the standard frontline therapy for patients with CML in early CP. 2nd generation TKIs (nilotinib, dasatinib) have been reported to be more effective than imatinib as frontline therapy in rates of response and transformation. Nilotinib has received regulatory approval for this indication and others (dasatinib, bosutinib) may come soon. Although fewer patients are expected to experience failure to therapy with the use of these agents, these patients will represent a management challenge. The characteristics, management and outcome of patients who fail therapy with 2nd generation TKI used as initial therapy has not been reported. Aim: To analyze the characteristics of patients who fail therapy with 2nd generation TKI used as initial therapy, their management, and outcome after failure to initial therapy. Methods: Two parallel studies of 2nd generation TKI as initial therapy for CML early CP are being conducted at MDACC, one with nilotinib and one with dasatinib. The study with nilotinib includes also patients in accelerated phase (AP) that have received no other prior therapy. The records of all patients who were taken off therapy from these trials were reviewed to investigate the reasons for failure, subsequent management and outcome. Results: A total of 172 pts have been treated with dasatinib (n=82) or nilotinib (n=90; 9 in AP) since 2005. After a median follow-up of 18.9 months, 23 pts (14%) have discontinued therapy: 13 (16%) pts in the nilotinib study (2 of them treated in AP), and 10 (12%) in the dasatinib study. Their median age 48 years (range:19–73) and they had received therapy with nilotinib or dasatinib for a median of 5.2 (0.03-48) months. Reasons for nilotinib treatment discontinuation include: toxicity 4 pts (elevated lipase, acute pancreatitis + atrial fibrillation, pericardial effusion and acute renal failure, one each), transformation to blast phase (BP) 3 pts (2 of them treated in AP), and other reasons 6 pts (2 each for insurance issues, patient request and non-compliance). Reasons for discontinuation of dasatinib include: toxicity 5 pts (2 pleural effusion, 1 prolonged thrombocytopenia, 1 bone pain, 1 congestive heart failure), 2 pts for loss of response, and 3 pts for pts' choice. Best response to frontline treatment with nilotinib or dasatinib was 6 (26%) pts major molecular response, 6 (26%) pts complete cytogenetic response, 1 (4%) pt partial cytogenetic response, 3 (13%) pts minor cytogenetic response, 1 (4%) pt with no response and 6 (26%) pts nonevaluable. At the time of failure 18 pts were in CP, 4 pts in BP (one pt transformed shortly after discontinuation) and 1 AP. At the time of treatment interruption, 14 pts had BCR-ABL sequencing and 2 were found to have mutations (F359C, Y253H); 3 pts had new additional chromosomal abnormalities (ie, clonal evolution). Subsequent treatment after failure to initial therapy include: imatinib in 8 pts, nilotinib in 2 pts, dasatinib 1 pt, Hyper CVAD with dasatinib 1 pt, Hyper CVAD with imatinib 1 pt, stem cell transplant 2 pts, bafetinib 1 pt, and unknown 4 pts (lost to follow-up). One pt died shortly after failure without further therapy. Best response to subsequent therapies were 1 pt with CMR (after stem cell transplant), 7 pts with MMR (3 pts after imatinib, 1 pt after dasatinib, 1 pt after nilotinib, 1 pt after Hyper CVAD with imatinib and 1 pt after stem cell transplant), 1 pt CHR, 1 pt minor CyR, 3 pts without response, and 8 pts were not evaluable. Of the 5 pts that achieved MMR with subsequent TKI, all were in CP and had discontinued initial therapy because of toxicity (4 pts) or personal reasons (1pt). Median duration of ongoing subsequent treatment is 8 months (range 1.7–25). The survival rate after a median follow-up of 3.9 months since failure to frontline therapy is 87%. Conclusion: Failure after frontline therapy with second generation TKI is an uncommon event, most frequently associated with toxicity or patient preference. Most of these patients respond well to alternative TKI. This adequate response should alleviate the fear of not having available effective therapy if patients fail to respond to 2nd generation TKI when used as frontline therapy. Disclosures: Kantarjian: BMS: Research Funding; NOVARTIS: Research Funding. Cortes:BMS: Research Funding; NOVARTIS: Research Funding; Pfizer: Consultancy, Research Funding.

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