scholarly journals 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 ◽  
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.

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

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3781-3781 ◽  
Author(s):  
Carlos G. Romo ◽  
Hagop M Kantarjian ◽  
Rajyalakshmi Luthra ◽  
Alfonso Quintás-Cardama ◽  
Elias J. Jabbour ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tyrosine Kinase ◽  
Research Funding ◽  
Initial Therapy ◽  
Molecular Response ◽  
Exon 2 ◽  
Free Survival ◽  
Significant Difference ◽  
Frontline Therapy

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.

scholarly journals A Report on 114 Patients Who Experienced Treatment Free Remission in a Single Institution during a 15 Years Period: Long Term Follow-up, Late Molecular Relapses and Second Attempts

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 27-27 ◽  
Author(s):  
Philippe Rousselot ◽  
Clémence Loiseau ◽  
Marc Delord ◽  
Caroline Besson ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Median Duration ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Molecular Response ◽  
Single Institution ◽  
Long Term Follow Up

Background. The A-STIM (According to Stop IMatinib, NCT1038732) observational study established the loss of major molecular response (loss of MMR, BCR-ABL1 IS &gt;0.1%) as a practical and safe criterion for restarting therapy in patients with CML who had stopped tyrosine kinase inhibitors after a prolonged (≥2 years) and sustained deep molecular response (J Clin Oncol. 2014;32(5):424-30). We focus now on the long-term prospective follow-up of a cohort of 114 patients from a single institution included in the A-STIM observatory in order to describe late events (late molecular relapses after 2 years or more in TFR and second TFR attempts). Methods: Adult chronic phase CML patients treated with tyrosine kinase inhibitors and in sustained (≥2 years) MR4.5 (BCR-ABL1 IS ≤0.0032%) were eligible. Patients with a previous history of resistance or mutations of the BCR-ABL tyrosine kinase domain were excluded. Molecular relapses were defined by loss of MMR. After TKI discontinuation, BCR-ABL transcripts were monitored monthly during the first 12 months, every 2-3 months during the 2nd year and every 3-6 months thereafter. Median follow-up from diagnosis of CML was 15.9 years. Results. Over a 15 years period, 114 patients followed at the Centre Hospitalier de Versailles were registered. Median age at diagnosis was 48.2 years, sex ratio was 0.5 and Sokal score distribution was 54%, 26% and 20% for the Low, intermediate and high-risk categories respectively. Median duration of TKIs before the first TFR attempt was 7.4 years. Thirty-six patients (31%) were previously treated with interferon, 62 (54%) received imatinib only and 52 (46%) were on 2G-TKIs at the time of discontinuation (13 as first line therapy and 39 after a switch for sub-optimal response or intolerance). Median follow-up in TFR1 was 5.4 years. TFR1 rates were 57.6% at 1 year, 53.8% at 3 years, 51.6% at 5 years and 44.5% after 7 years. The longest duration of ongoing TFR1 is 14.9 years. The duration of TKIs and the duration of MR4.5 were associated with a higher TFR1 rate; a trend was observed for previous exposure to interferon. Patients on 2G-TKIs (first or second line) had similar TFR1 rates as compared to patients on imatinib. Fifty-seven patients relapsed including 8 patients (14%) experiencing late molecular relapses. Of those, 4 patients relapsed after 5 years. The latest molecular relapse was observed after 6.4 years. In late relapsing patients, MR4.5 was lost after 10 months in median and MR4 after 22 months with a long-lasting period of fluctuations of the BCR-ABL1 ratio in-between MR4 and MR3 (a focus on patients with fluctuations of the BCR-ABL1 ratio will be presented at the congress). Out of the 57 patients who restarted a TKI, 31 patients (54%) experienced a second attempt. Median duration of TKIs between TFR1 and TFR2 was 2.9 years and total exposure to TKIs before TFR2 was 9 years. Fifteen patients (48%) were on imatinib before TFR2 whereas 16 where on 2G-TKI (52%). Median follow-up in TFR2 was 3.4 years. TFR2 rates were 53.9% at 1 year, 45.6% at 3 years and 39.9% after 5 years. The longest TFR2 is 9 years. No factor was associated with TFR2 duration, a switch to 2G-TKIs did not provide any advantage. Seventeen patients relapsed including 3 patient (17%) experiencing late molecular relapses. Anecdotally, 5 patients went to a third TFR attempt and 1 is in TFR3 for 5.2 years. Conclusion. Based on a 15 years' experience we were able to report on long term follow-up in TFR1 and in TFR2. Among patients experiencing molecular relapses, we observed 14% and 17% late relapses after more than 2 years after TFR1 and TFR2 respectively, suggesting that a long-term molecular follow-up is mandatory for CML patients in TFR. Figure Disclosures Rousselot: Incyte: Research Funding; Pfizer: Research Funding. Cayuela:Incyte: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

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

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

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

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

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

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

Different Definitions of Progression-Free Survival (PFS) and Event-Free Survival (EFS) May Result In Perceived but Not Real Differences In Long-Term Outcome When Comparing Trials In Chronic Myeloid Leukemia (CML)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 672-672
Author(s):  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Elias Jabbour ◽  
Jianqin Shan ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Research Funding ◽  
Chronic Phase ◽  
Patient Choice ◽  
Imatinib Therapy ◽  
Free Survival ◽  
Blastic Phase ◽  
Resistance Loss ◽  
Frontline Therapy

Abstract Abstract 672 Background The favorable results of second generation tyrosine kinase inhibitors (TKIs; nilotinib, dasatinib) in frontline therapy of Philadelphia chromosome (Ph) positive-CML may establish them as new standards in frontline therapy. This depends on the maturing data with the long-term endpoints of PFS and EFS. Different definitions are used to define “progression” and “event” in different studies. This may result in perceived but not real differences in outcomes with various TKIs when comparing trials. In addition, multi-institutional sponsored trial designs may compound the variable definitions: 1) patients taken off study for occurrences other than the defined “progression” or “event” (eg toxicity, intolerance, other) are censored at the time they are off therapy and not coded for progression/event/death once they are off TKI; and 2) such studies have limited capacities to follow up patients for progression/event after they are off drug therapy for more than 30–60 days. Single institutional studies have a potential advantage of continuing to monitor patients for progression/events after they are off the particular protocol TKI. Study Aim To analyze the impact of differences in the definitions of PFS and EFS used in the IRIS, ENEST-nd, DASISION, and M.D. Anderson (MDACC) trials on outcome, when these definitions are applied to patients with newly diagnosed CML treated with TKIs on MDACC studies. Patients and Methods 435 patients (July 2000-April 2010) with early chronic phase Ph-positive CML treated with imatinib (n=281), nilotinib (n=78), and dasatinib (n=76)were analyzed for outcome using different definitions. Definitions were: 1) PFS- ENEST: progression = accelerated or blastic phase (AP-BP) on nilotinib/imatinib therapy + CML related death on nilotinib/imatinib therapy or within 30 days off therapy; 2) EFS-IRIS: event = progression to AP-BP on imatinib + death of any cause on imatinib + loss of CHR or major CG response; 3) PFS-DASISION: progression = EFS-IRIS definition + WBC increase to more than 20; deaths are coded on dasatinib and within 60 days off dasatinib; 4) EFS MDACC: event = progression to AP-BP + loss of major CG response +resistance/loss of CHR/lack of achievement of response by ELN criteria + off for toxicity + death from any cause on or off therapy (if not counted prior to death as progression/event). Results The median follow-up is 67 months (2-116). Of the 435 patients treated, 312 (72%) remain on TKI therapy; 123 (28%) were taken off for the following reasons: resistance/loss of response n = 33; blastic phase on TKI therapy n=6; intolerance/toxicity n= 29; other causes n = 55. Reasons off for the latter 55 patients are: lost to follow – up (n=14); non-compliance (n=11); financial issues (n=8): intercurrent illness (n=7); patient choice (n=5); referral to SCT in chronic phase (n=2); and death from non-CML cause (n=8: 1 complications of surgery, 2 old age, 1 CHF, 1 pneumonia, 2 car accident/suicide, 1 cardiac infarction). So far, 33 patients (7.6%) have died; 8 while on TKI therapy (none from CML; detailed earlier); 2 within 60 days off TKIs (1 AML, 1 renal cancer); and 23 off TKIs for > 60 days. Deaths in the latter 23 were from: 10 post resistance/relapse/BP (accounted for as event/resistance at time off TKI); 10 taken off for toxicity/intolerance (censored at time off; 8 deaths later from CML, 1 post SCT, 1 unknown); 4 off for other illness/non-compliance/lost to FU/pt choice (3 deaths later from CML; 1 from other). Thus, of the 33 deaths, only 19 (8 deaths on TKI + 2 deaths within 60 days + 9 off for resistance/relapse/BP) would be counted as progression/events on the IRIS/ENEST/DASISION studies while 14 would be censored at time off TKI. Based on these 4 definitions, the number of progression/events were: PFS-ENEST 26 progressions; EFS-IRIS 40 events; PFS-DASISION 43 progression/events; EFS-MDACC 76 events. The corresponding 5-year PFS EFS rates were 93%, 90%, 89%, and 81%. (Figure) Conclusions With the importance of EFS and PFS in determining whether new TKIs are better than imatinib in frontline therapy, precise and common definitions of these endpoints across randomized clinical trials and single institutional trials are needed. Randomized multi-institutional trials may not collect accurately all events after patients are off TKI therapy for 30–60 days. Disclosures: Kantarjian: Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. O'Brien:Novartis: Research Funding; BMS: Research Funding. Kadia:Novartis: Membership on an entity's Board of Directors or advisory committees. Cortes:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Pfizer: Consultancy.

ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 92-92 ◽  
Author(s):  
Giuseppe Saglio ◽  
Andreas Hochhaus ◽  
Timothy P. Hughes ◽  
Richard E. Clark ◽  
Hirohisa Nakamae ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Eligibility Criterion ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Vascular Events ◽  
Advisory Committees ◽  
The Impact

Abstract Introduction Frontline NIL continues to show benefit over IM in pts with Philadelphia chromosome-positive (Ph+) CML-CP, with higher rates of major molecular response (MMR; BCR-ABLIS ≤ 0.1%) and MR4.5 (BCR-ABLIS ≤ 0.0032%), lower rates of progression to accelerated phase (AP)/blast crisis (BC) and fewer new BCR-ABL mutations on treatment in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Pts (ENESTnd) trial. Here, we report data with a minimum follow-up (f/u) of 4 y; updated data based on 5 y of f/u will be presented. Methods Adults with newly diagnosed Ph+ CML-CP (N = 846) were randomized to NIL 300 mg twice daily (BID; n = 282), NIL 400 mg BID (n = 281), or IM 400 mg once daily (QD; n = 283). Progression and overall survival (OS) events were collected prospectively during study f/u, including after discontinuation of study treatment. Efficacy in the NIL 300 mg BID and IM arms was evaluated based on achievement of EMR (BCR-ABLIS ≤ 10% at 3 mo). Results At 4 y, ≥ 87% of pts remained on study in each arm and 57%-69% remained on core treatment (Table). Rates of MMR and MR4.5 by 4 y were significantly higher with NIL vs IM. Significantly fewer pts progressed to AP/BC on NIL vs IM (on core treatment: 0.7%, 1.1%, and 4.2%; on study: 3.2%, 2.1%, and 6.7% [NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively]). Of 17 pts across the 3 arms who progressed on core treatment, 11 (65%) had never achieved complete cytogenetic response and none had achieved MR4.5. Fewer mutations have emerged in the NIL arms vs the IM arm; in y 4, mutations emerged in 2 pts (1 pt with T315I on NIL 300 mg BID; 1 pt with F317L on IM). More pts achieved EMR in the NIL 300 mg BID arm vs the IM arm (91% vs 67%). Pts with EMR had significantly higher rates of progression-free survival (PFS) and OS at 4 y vs pts with BCR-ABL > 10% at 3 mo. Among pts with BCR-ABL > 10% at 3 mo, more progressions to AP/BC occurred in the IM arm (n = 14) vs the NIL 300 mg BID arm (n = 2); half of these pts progressed between 3 and 6 mo. In pts with intermediate or high Sokal risk, PFS and OS at 4 y were higher in both NIL arms vs the IM arm. No new safety signals were detected. Selected cardiac and vascular events were more common on NIL vs IM (by 4 y, peripheral arterial occlusive disease [PAOD] in 4 [1.4%], 5 [1.8%], and 0 pts; ischemic heart disease [IHD] in 11 [3.9%], 14 [5.1%,] and 3 [1.1%] pts; and ischemic cerebrovascular events in 3 [1.1%], 5 [1.8%], and 1 [0.4%] pts in the NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively). In the NIL 300 mg BID arm, 2 of 11 IHD events occurred between 3 and 4 y (all 4 PAOD events occurred in the first 2 y). In the NIL 400 mg BID arm, 2 of 5 PAOD events and 3 of 14 IHD events occurred between 3 and 4 y. Most pts (7 of 9) with a PAOD event on NIL were at high risk due to a combination of baseline risk factors. Conclusions NIL, a standard-of-care frontline therapy option for newly diagnosed CML-CP pts, affords superior efficacy compared with IM, including higher rates of EMR (which is associated with improved long-term outcomes), higher rates of MR4.5 (a key eligibility criterion for many studies of treatment-free remission), and a lower risk of disease progression. NIL continues to show good tolerability with long-term f/u. While selected cardiac and vascular events (including PAOD) are slightly more frequent on NIL vs IM, no increase in annual incidence of these events over time has been observed. Disclosures: Saglio: ARIAD: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Hochhaus:Ariad: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Hughes:Ariad: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CSL: Research Funding. Clark:Pfizer: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Nakamae:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau, travel/ accomodations/ meeting expenses Other. Kim:BMS, Novartis,IL-Yang: Honoraria; Pfizer: Consultancy, Research Funding. Etienne:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Flinn:Novartis: Research Funding. Lipton:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Moiraghi:Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Fan:Novartis: Employment. Menssen:Novartis: Employment. Kantarjian:Novartis: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; ARIAD: Research Funding. Larson:Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy.

Significance of ELN Provisional Response Definitions In Predicting Long-Term Outcomes of Patients with CP-CML Treated with Dasatinib After Imatinib Failure.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3439-3439
Author(s):  
Jorge E. Cortes ◽  
Neil P. Shah ◽  
Charles A. Schiffer ◽  
Philipp D. LeCoutre ◽  
Giuseppe Saglio ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Long Term Outcomes ◽  
Free Survival ◽  
Optimal Response ◽  
Response Table ◽  
Starting Dose

Abstract Abstract 3439 Introduction: The European LeukemiaNet (ELN) recommendations for the management of chronic phase chronic myeloid leukemia (CP-CML) have provisionally defined criteria for suboptimal and failure to second-generation tyrosine kinase inhibitors (TKIs) (Baccarani et al., J Clin Oncol. 27 (35):6041-51, 2009). We tested the significance of these definitions in 3 studies of dasatinib after imatinib failure. Methods: Data from 1150 treated patients (pts) included in the 3 studies [CA180-013 (n=387); dasatinib only arm of CA180-017 (n=101); CA180-034 (n=662)] were analyzed. For the purpose of this analysis, we modified the 2009 ELN recommendations to add an optimal response category as shown in Table 1. Background: The median age of the pts included in this analysis was 56 yrs (range, 18–85) and the median duration of CML in these pts was 58 months (range, 0.9–250.8). Thirty-eight percent of the pts had received imatinib at a dose > 600mg/day and 45% had been on imatinib therapy >3 yrs. Twenty-four percent of pts included in this analysis had demonstrated imatinib-intolerance. Thirty-five percent of pts had mutations before the start of dasatinib therapy (5% had T315l). Results: Rates of optimal response at 3, 6 and 12 months were 51%, 44% and 36%. Rates of suboptimal response at 3, 6 and 12 months were 7%, 16% and 27%. Rates of failure response at 3, 6 and 12 months were 29%, 34% and 37%. Rates of warning response at 3 and 6 months were 12% and 6%. The starting dose of dasatinib did not influence these response rates. The group defined as suboptimal at 12 months (of whom 52% had already achieved CCyR) had a higher probability of achieving CCyR within 2 yr (83%) compared to the groups defined as suboptimal at 6 months (69%) or 3 months (51%). This suboptimal group at 12 months also had a higher 2 yr progression-free survival (PFS) (92%) compared to the suboptimal groups at 6 months (82%) and 3 months (80%). The probability of achieving an MMR within 2 yr was slightly higher in pts defined as optimal at 6 months (80%) vs. those at 3 months (71%). However, the probability of achieving an MMR within 2 yr showed minimal change for the suboptimal (31-35%) or the failure (5%) response groups defined at 3, 6 and 12 months. The pts with a warnings response had a profile that was intermediate between suboptimal and failure response. Table 2 summarizes 2 yr outcomes based on response. Conclusions: These results suggest that the 2009 ELN provisional response definitions may be helpful in predicting long term outcomes in pts receiving second-line dasatinib therapy. In this cohort of pts, optimal responders identified themselves rapidly as did pts with failure. However, the outcome of pts defined as suboptimal at 12 months appeared more favorable than that of pts defined as suboptimal at 3 and 6 months. This, in addition to the higher proportion of pts classified as suboptimal at 12 months, compared to those classified as suboptimal at 3 and 6 months, may suggest that the ELN defined cut-off between optimal vs. suboptimal at 12 months (i.e. MMR) may need to be modified in order to make the prognosis for suboptimal response more consistent across different time points. Pts classified in the warnings category at 3 and 6 months had an outcome intermediate between those with suboptimal and failure response. Disclosures: Cortes: Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Shah:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Ariad: Consultancy. LeCoutre:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Kantarjian:Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. Jabbour:GlaxoSmithKline: Research Funding. Bahceci:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Lambert:Bristol-Myers Squibb: Employment. Guilhot:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy.

scholarly journals L-Asparaginase Toxicity in the Treatment of Children and Adolescents with Acute Lymphoblastic Leukemia

2021 ◽  
Vol 10 (19) ◽  
pp. 4419
Author(s):  
Madalina-Petronela Schmidt ◽  
Anca-Viorica Ivanov ◽  
Daniel Coriu ◽  
Ingrith-Crenguta Miron
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Children And Adolescents ◽  
Lymphoblastic Leukemia ◽  
Event Free Survival ◽  
Long Term Outcomes ◽  
Term Survival ◽  
Free Survival ◽  
The Impact

Asparaginase is a basic component of chemotherapy in pediatric acute lymphoblastic leukemia (ALL) and has played a crucial role in improving the long-term survival of this disease. The objectives of this retrospective study were to elucidate the toxicity profile associated with asparaginase in children and adolescents with ALL, to analyze the impact of each type of toxicity on long-term outcomes, and to identify risk factors. We analyzed the medical charts of 165 patients diagnosed with ALL at Sf. Maria Iasi Children’s Hospital from 2010 to 2019 and treated according to a chemotherapeutic protocol containing asparaginase. The median duration of follow-up was 5 years (0.1–11.5 years). Groups of patients with specific types of toxicity were compared to groups of patients without toxicity. We found the following incidence of asparaginase-associated toxicity: 24.1% clinical hypersensitivity, 19.4% hepatotoxicity, 6.7% hypertriglyceridemia, 4.2% hyperglycemia, 3.7% osteonecrosis, 3% pancreatitis, 2.4% thrombosis, and 1.2% cerebral thrombosis. Overall, 82 patients (49.7%) had at least one type of toxicity related to asparaginase. No type of toxicity had a significant impact on overall survival or event-free survival. Being older than 14 years was associated with a higher risk of osteonecrosis (p = 0.015) and hypertriglyceridemia (p = 0.043) and a lower risk of clinical hypersensitivity (p = 0.04). Asparaginase-related toxicity is common and has a varied profile, and its early detection is important for realizing efficient and appropriate management.

scholarly journals Cessation of Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients with Deep Molecular Response: Results of the Euro-Ski Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 787-787 ◽  
Author(s):  
Francois-xavier Mahon ◽  
Johan Richter ◽  
Joelle Guilhot ◽  
Henrik Hjorth-Hansen ◽  
Antonio Almeida ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Treatment Duration ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
P Value ◽  
Molecular Response ◽  
Free Survival ◽  
Tki Treatment

Abstract Background: Tyrosine kinase inhibitors (TKI) have dramatically improved survival in chronic myeloid leukemia (CML) with a high proportion of patients reaching deep molecular responses (DMR). The effectiveness of stopping TKI treatment is a key question regarding the management of CML. Actually, in several studies, it has been proven that a substantial part of patients in DMR can safely and successfully stop TKI therapy. However, the exact preconditions for stopping CML treatments are not yet defined. This is the aim of the European stop TKI (EURO-SKI) trial (ClinicalTrials.gov numbers: NCT01596114). Methods: Chronic phase CML patients without prior TKI failure, treated with either imatinib, nilotinib or dasatinib, in DMR (BCR-ABL <0.01% on the international scale, MR4) for the duration of at least one year were proposed to stop TKI treatment. Molecular recurrence (MR) was defined by the loss of the major molecular response (MMR, BCR-ABL <0.1% IS) at any one point. We estimated molecular recurrence-free survival (MRFS) with the Kaplan-Meier method. The potential prognostic values for MR were tested by univariate and multivariable analyses and the cut-off was identified with the minimal p-value approach. Results: From June 2012 to December 2014, 821 CP CML patients were included in 11 European countries belonging to the European Leukemia Net (ELN). 750 patients had assessable molecular data (European standardization according to Cross et al, Leukemia 2012) for the estimation of MRFS. Of these patients, 348 lost MMR and 5 died in remission ; MRFS was 62% (95% confidence interval (CI): 59% - 67%) at 6 months (m), 56% (CI: 52% - 59%) at 12 m and 52% (CI: 48% - 56%) at 24 m on an "Intention to Treat Basis ". At the time of evaluation most patients regained DMR, and importantly, no progression to advanced disease phase was noted. A prognostic modelling was performed based on 448 patients treated with imatinib. Univariate analysis showed no significant association between age, gender, depth of molecular response (MR4.5 vs. no MR4.5) or any variable part of the Sokal, EURO, EUTOS, or ELTS scores and MMR status at 6 months after treatment stop. Treatment duration with imatinib and MR4duration prior to the stop were significantly (p<0.001) correlated with MMR status at 6 months. The odds ratio for treatment duration was 1.16 (95%-CI: 1.08-1.25), meaning that one additional year of treatment increases the odds to stay in MMR at 6 months by 16%. Molecular relapse-free survival at 6 months was 65.5% for imatinib treatment > 5.8 years and 42.6% for treatment ≤ 5.8 years. This cut-off was identified with the minimal p-value approach. A true pharmaco-economic study will be necessary but taking into account the number of months without treatment in 603 patients, Imatinib front line (with a median observation time of 24 m for patients still off treatment) and the cost of imatinib in each of the 11 European countries (range: 1.734-3.370 Euro per month) the total estimated savings amounted to 27.85 million Euro. Conclusion: Using standardized molecular monitoring, stopping TKI therapy in a very large cohort of CML-patients appears feasible and safe and high MRFS rates are achievable. Longer duration of imatinib-therapy (optimal ≥ 5.8 years) prior to TKI-stop is associated with a higher probability of MRFS. Taking into account the long follow-up without molecular relapse in the historical studies such as STIM1 (Etienne et al; JCO 2016) the "operational" cure of CML with oral TKI is an up-to-date issue. Disclosures Mahon: NOVARTIS PHARMA: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; PFIZER: Honoraria; ARIAD: Honoraria. Richter:Ariad: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Almeida:BMS: Speakers Bureau; Shire: Speakers Bureau; Alexion: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Berger:NOVARTIS PHARMA: Honoraria. Machova Polakova:Bristol Myers-Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Honoraria, Research Funding. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Saussele:NOVARTIS PHARMA: Consultancy, Honoraria; BMS: Honoraria.

Oral Fludarabine and Intravenous Rituximab (FR) for Chronic Lymphocytic Leukemia (CLL): Long Term Outcomes and Secondary Malignancies in 673 Patients Treated in British Columbia (BC)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4300-4300
Author(s):  
Elysha Vanderveer ◽  
Steven J.T. Huang ◽  
Helene Bruyere ◽  
Tanya Gillan ◽  
Charles H. Li ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Secondary Malignancies ◽  
Long Term Outcomes ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
The Impact

Background: Oral fludarabine and intravenous rituximab (FR) was the standard first-line therapy for CLL or small lymphocytic lymphoma (SLL) patients (pts) in BC from 2003-2015. Ibrutinib for relapsed/refractory (R/R) CLL was introduced and publicly funded in 2015. Our aim was to review long term outcomes of all CLL/SLL pts treated with FR in BC, including the impact of 2nd line therapy with ibrutinib versus chemoimmunotherapy and to report the risk of secondary malignancies in this population based cohort. Methods: The BC Provincial CLL Database was used to identify all CLL/SLL pts who received first-line FR from 2003-2017. The BC Cancer Registry was used to identify secondary malignancies occurring after FR. Primary outcomes were overall survival (OS) and treatment free survival (TFS), defined as start of FR to next-line therapy or death/last follow-up. Variables examined for impact on OS/TFS included age at FR, gender, primary diagnosis (CLL vs SLL), B symptoms, advanced stage (Rai stage 3-4 CLL, Ann Arbor 1-2 SLL), baseline hemoglobin, lymphocyte count, platelets, LDH and FISH abnormalities. All variables significant on univariate analyses (P<.1) were included in multivariate Cox proportional hazard regression models to identify significant predictors of OS/TFS. Results: 673 pts were identified as receiving FR as first-line therapy for CLL (86%) or SLL (14%). Median time from CLL/SLL diagnosis to FR was 2.5 years (y) (range 0.1-27.3). Median age at FR was 67 y (range 26-91) with 73% ≥ 60 y and 39% ≥ 70 y. Most pts were male (66.1%), had early stage disease (84.2%) with no B symptoms (89.7%) and normal LDH (81.1%). Of 411 pts with pre-treatment FISH testing, prevalence of FISH abnormalities were: 48.5% del13q, 25.7% trisomy 12, 12.9% del11q, 8.0% del17p. Median number of FR cycles was 6 (range 1-10). Median follow-up of living pts from FR was 6.4 y (range 0.2-12.7). 2 y and 5 y OS were 89.4% (95% CI: 86.8-91.6) and 73% (95% CI: 69.0-76.6) respectively; median OS 11.6 y (95% CI: 4.6-13.7 y). 2 y and 5 y TFS were 72% (95% CI: 68-75%) and 37% (95% CI: 33 - 41) respectively, median TFS 3.8 y (95% CI: 1.78-7.09). Those with del17p had significantly worse OS and TFS compared to those without (median OS 5.7 vs 13.7 y, P<.001; median TFS 1.4 vs 3.9 y, P<.001), Fig. 1. Multivariate analysis identified only del17p (HR 4.35, 95%CI: 2.10-9.01, P<.001) and age at FR (HR 1.04, 95% CI: 1.01-1.07, P=.007) as significant predictors of OS, and del17p (HR 4.3, 95% CI: 2.5-7.5, P<.001) as a significant predictor of TFS. During the follow up period, 351 pts (52%) went on to 2nd-line therapy: ibrutinib 87 (including 2 with BR and 1+R), cyclophosphamide-based (CVP/CHOP) +/- R 102, repeat FR 71, FCR 6, F alone 21, bendamustine +/-R 13, chlorambucil+/-R 38, steroids 3, R alone 3, alemtuzumab 2, other chemotherapy 3 and allotransplant 2. Median follow-up after 2nd-line therapy was 2.8 y (range 0.1-10.8). Median OS and TFS from 2nd-line treatment (TFS2) for ibrutinib (n=87) vs. for other treatments (n=264) was: OS not reached vs 5.3 y, P<.001; TFS2 not reached vs 1.2 y, P<.001. These significant differences persisted when analyses were restricted to those who received ibrutinib vs. chemoimmunotherapy (n=169): median OS not reached vs. 6.3 y (P=.002); median TFS not reached vs. 1.7 y (P<.001), Fig. 2. 2 y OS and TFS2 after ibrutinib were 91% (95% CI: 80-96%) and 78% (95% CI: 65-87%), respectively. A total of 202 malignancies were recorded after initiation of FR in 166 pts (24.7%), Table 1. The median time from FR to 2nd malignancy was 2.3 y (range 0.1-13.5). Richter's transformation (RT) occurred in 36 pts (5.3%) at median 1.9 y (range 0.1-13.2) from FR. Most frequent 2nd malignancies were: non-melanoma skin cancer (11.7%), lung (2.5%), colon (2.1%), other heme (1.9%), and prostate (1.8%). There were 4 cases of acute myeloid leukemia (AML), 2 of which received alkylator therapy after FR prior to AML diagnosis. Conclusions: In this large, homogeneous cohort of CLL/SLL pts treated with first-line FR, including nearly 40% of pts ≥ age 70, we demonstrate a short median TFS of 3.8 y; however, a long OS of 11.6 y. Rates of 2nd malignancies are low after this non-alkylator based chemoimmunotherapy regimen. Ibrutinib for R/R CLL/SLL after FR resulted in significantly improved survival over alternate therapy, with excellent 2 yr OS 91% and TFS 78%. These data demonstrate the efficacy of FR and the benefit of ibrutinib over chemoimmunotherapy as second-line therapy for CLL/SLL in the real-world. Disclosures Bruyere: Jenssen: Other: Travel Grant; Celgene: Honoraria. Villa:Roche, Abbvie, Celgene, Seattle Genetics, Lundbeck, AstraZeneca, Nanostring, Janssen, Gilead: Consultancy, Honoraria. Scott:Celgene: Consultancy; Roche/Genentech: Research Funding; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Savage:BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria; Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Connors:Takeda Pharmaceuticals: Honoraria; Seattle Genetics: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy. Sehn:TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria. Gerrie:Lundbeck, Seattle Genetics: Consultancy, Honoraria.

Sign in / Sign up

Export Citation Format

Share Document