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.

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.

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.

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.

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.

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

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

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

Event-Free Survival at 12 Months and Subsequent Overall Survival in Patients with Peripheral T-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1501-1501
Author(s):  
Matthew J Maurer ◽  
Fredrik Ellin ◽  
James Cerhan ◽  
Stephen Ansell ◽  
Brian K Link ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
T Cell Lymphomas

Abstract Background: Peripheral T-Cell lymphomas (PTCLs) constitute approximately 10% of lymphoid malignancies and consist of several distinct entities based on pathologic and clinical characteristics. With the exception of a few subtypes (e.g., ALK-positive anaplastic large cell lymphoma (ALCL) and some primary cutaneous or leukemic forms of PTCL), a majority of PTCLs are aggressive as characterized by poor treatment response, rapid disease progression and poor overall survival. We have shown that landmark timepoints of event-free survival after diagnosis can stratify subsequent overall survival (OS) in diffuse large B-cell and follicular lymphoma. Here we evaluate this approach in newly diagnosed aggressive PTCLs treated with anthracyline-based or related chemotherapy. Methods. Newly diagnosed PTCL patients were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2012. Clinical data were abstracted from medical records using a standard protocol. For this analysis, we included patients receiving anthracycline-based or other multiagent chemotherapy for the following PTCL subtypes: ALK-negative ALCL (N=24); angioimmunoblastic T-cell lymphoma (AITL, N=34); PTCL, not otherwise specified (NOS; N=60); enteropathy-associated T-cell lymphoma (EATL, N=8); extranodal NK/T-cell lymphoma, nasal type (ENKTL, N=11); and hepatosplenic T-cell lymphoma (HSTCL, N=1). Patients were prospectively followed, and event-free survival (EFS) was defined as time from diagnosis to progression, re-treatment, or death due to any cause. Landmark EFS timepoints were assessed at 12 (EFS12) and 24 (EFS24) months after the date of diagnosis. Subsequent OS was defined as time from a specific endpoint (diagnosis, event or EFS landmark). Replication was performed in a population-based cohort of T-cell lymphomas diagnosed from 2000-2009 from the Swedish Lymphoma Registry. Results. 138 eligible patients were enrolled in the MER from 2002-2012, the median age at diagnosis was 58 years (range, 19-88), 66% were male, 73% had Stage III-IV disease, and 33% had IPI 0-1. At a median follow-up of 47 months (range 11-120), 87 patients (63%) had an event and 70 patients (51%) had died. From diagnosis, only 60 patients were event-free at 12 months (EFS12 45%). Patients who failed to achieve EFS12 had a poor subsequent OS from event (median OS = 6.8 months, 95% CI: 5.3-14.0, figure 1). In contrast, patients who achieved EFS12 had a favorable subsequent OS (median unreached, figure 2). Of the 427 eligible patients in the Swedish registry, the median age at diagnosis was 66 years (range, 18-88), 63% were male, 68% had Stage III-IV disease, and 25% had IPI 0-1. PTCL subtypes were: ALK-negative ALCL (N=89); AITL (N=80); PTCL, NOS (N=183); EATL (N=44); ENKTL (N=24); and HSTCL (N=7). At a median follow-up of 86 months (range 40-158), 333 patients (79%) had an event and 316 patients (74%) had died. From diagnosis, 183 patients were event-free at 12 months (EFS12 44%). Similar to the MER cohort, Swedish patients failing EFS12 had poor subsequent survival (median OS = 3.7 months, 95% CI: 2.9-5.3, figure 1). Swedish patients achieving EFS12 had a favorable subsequent OS (median OS = 89 months, figure 2). Similar results were obtained when conducting landmark analysis at 24 months after diagnosis (EFS24). Conclusion. Relapse and re-treatment events within the first 12 months of diagnosis are associated with very poor OS in PTCL treated with anthracyclines or related chemotherapy, while patients achieving EFS12 have encouraging subsequent OS. Stratifying patients into prognostically distinct subsets using EFS12 may help focus biologic and biomarker studies. EFS12 has potential as an early endpoint for studies of newly diagnosed PTCL. Further investigation of determinants related to post-EFS12 survival is needed. Disclosures Maurer: Kite Pharma: Research Funding. Cerhan:Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding. Relander:Respiratorius: Patents & Royalties: valproate for DLBCL.

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

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

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

Frontline Hyper-CVAD with Ponatinib for Patients (pts) with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia: Results of a Phase II Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2496-2496
Author(s):  
Koji Sasaki ◽  
Susan O'Brien ◽  
Farhad Ravandi ◽  
Deborah A Thomas ◽  
Haim G Moore ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Time ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Event Free Survival ◽  
Vascular Events ◽  
Free Survival ◽  
Philadelphia Chromosome Positive

Abstract Background: Addition of tyrosine kinase inhibitors (TKIs) to chemotherapy improves outcome in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is a more potent BCR-ABL inhibitor, and covers the T315I clones. The combination of hyper-CVAD with ponatinib may contribute to better response rates and higher likelihood of eradication of minimal residual disease (MRD) than those reported with other TKIs. Methods: Pts with newly diagnosed Ph+ ALL received 8 cycles of hyper-CVAD alternating with high dose methotrexate and cytarabine every 21 days. Ponatinib was given at 45 mg/day for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Pts in CR received maintenance with ponatinib 45 mg/day and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. Results: From 11/2011 to 9/2013, 34 pts with untreated Ph+ ALL and 3 pts previously treated (2 pts not in CR were treated with one cycle of chemotherapy before the detection of BCR-ABL1; 1 pt in CCyR after 2 cycles of chemotherapy and dasatinib) have received a median of 6 cycles (2-8); 13 are receiving maintenance in CR; 9 underwent ASCT after a median of 4 cycles. Baseline pt characteristic and outcome are described in table 1. The overall CCyR, MMR, and CMR rates were 100%, 95%, and 78%, respectively. The median time to MMR and CMR were 3 (range, 2-14) and 11 (range, 2-96) weeks, respectively. The median time to MRD negativity was 3 weeks (range, 3-14). Median time to platelet and neutrophil recovery for cycle 1 was 22 and 18 days, respectively, and 22 and 16 days for subsequent cycles. Grade ≥ 3 toxicity included infections during induction (54%), increased liver functional tests (38%), thrombotic events (8%), myocardial infarction (14%), hypertension (16%), skin rash (22%), and pancreatitis (22%). With a median follow up of 26 months, 29 (78%) remain alive and in CR. Six pts died in CR: 1 pt died in CR from an unrelated cardiac event after being taken off therapy and placed on imatinib, 1 from MOF (C2D13), 1 from NSTEMI (C2D41; ponatinib 45 mg daily), 1 from potential MI (C4D42; ponatinib 30 mg daily), 1 from head injury sustained after a fall (C4D13), and 1 from sepsis post ASCT. Two (5%) in CMR relapsed with no identifiable T315I mutations after a median of 18 months. One of these pts achieved a second CR after blinatumomab and dasatinib therapy. To date, 13 pts are receiving maintenance therapy in CR. After the increased incidence of vascular toxicities was recognized, we offered our pts the option to switch TKIs or to reduce the dose of ponatinib to 30 mg and further decreased to 15 mg in pts in CMR. Thirteen pts remained on ponatinib at a dose of 15 mg daily in 12 and 30 mg daily in 1 (transcript levels of 0.04%). No further vascular events were observed in pts receiving lower doses of ponatinib. Nine pts elected to switch TKIs to dasatinib (n=7), nilotinib, or imatinib (1 each). One pt was lost to follow-up. Of 9 patients who underwent ASCT while in first CR (7 with MMR and 2 with CMR before transplantation), all but one are alive and disease-free after transplantation. There was no difference in OS by whether patients were censored or not at the time of ASCT. After transplantation, TKI therapy was resumed in all but one patient (1 imatinib, 4 dasatinib, 1 nilotinib, and 1 ponatinib). The 2-year event-free and overall survival rates are 81% and 80%, respectively (Figures 1). Conclusion: The combination of hyperCVAD with ponatinib is highly effective in pts with Ph+ ALL. Due to the vascular events observed, the ponatinib dose was modified to 30 mg daily during consolidation with subsequent reduction to 15 mg in pts in CMR without further episode of cardiovascular events. Table 1. Patient characteristic and outcome N(%); Median [range] N= 37 Age (yr) 51 [27-75] Age ≥50 20 (54%) Age ≥60 12 (32%) Performance status, No. (%)  0-1 31 (84)  2 6 (16)  WBC (x 109/L) 8 [1-630]  Presence of CNS disease, No. (%) 3 (8)  CD20 positivity, No. (%) 11 (30) Type of BCR-ABL1 transcript, No. (%)  p190 27 (73)  p210 10 (27) Cytogenetics abnormality, No. (%)  Diploid 5 (14)  Philadelphia-chromosome positive 32 (86) Baseline cardiovascular risk factors, No. (%)  Hypertension 18 (49)  Dyslipidemia 4 (11)  Coronary artery disease 4 (11)  Peripheral arterial disease 1 (3) Overall response, No. (%)  CR 36/36 (100)  CCyR 32/32 (100)  MMR 35/37 (95)  CMR 29/37 (78)  Flow negativity 35/36 (97)  Early death 0 Figure 1. a) Event-free survival, b) overall survival Figure 1. a) Event-free survival, b) overall survival Disclosures O'Brien: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; BMS: Consultancy, Research Funding; Teva: Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Chahoud:American Society of Hematology (ASH): Other: 2015 HONORS Award recipient. Wierda:Glaxo-Smith-Kline Inc.: Research Funding; Celgene Corp.: Consultancy.

scholarly journals TKI Treatment Discontinuation: How Many Patients Could Stop Tyrosine Kinase Treatment According to Discontinuation Trials Criteria? Incidence and Prognostic Impact of Deep Molecular Response in a Cohort of Chronic Myeloid Leukemia Patients of South Brazil's Hematology Centers

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5542-5542
Author(s):  
Laura Fogliatto ◽  
Marcelo Eduardo Zanella Capra ◽  
Mariza Shaan ◽  
Tito Vanelli Costa ◽  
Luis Carlos Zanandrea Contin ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Event Free Survival ◽  
Free Survival ◽  
The Future ◽  
Tki Discontinuation

Abstract Sustained deep molecular response (MR4.5) after imatinib treatment defines a subgroup of patients with chronic myeloid leukemia (CML) with better outcome and that probably would be able to stop treatment in the future, according to results of clinical TKI discontinuation trials. Most of these trials showed that patients with a long-term imatinib treatment and low Sokal risk have a higher probability of maintain a deep molecular remission after stopping treatment. OBJECTIVES The main objective is to review the molecular responses, overall survival and event free survival of CP CML patients that have been treated with imatinib in 14 hematology centers in South Brazil. Using our data basis we also would like to see how many of them present long-term imatinib treatment, sustained deep molecular remission and correlate these findings with the Sokal risk groups. These data would allow us to predict patient profile that could be able to discontinue the treatment in the future in a prospective clinical trial. PATIENTS AND METHODS This is a retrospective study in a cohort of pts with chronic myeloid leukemia chronic phase (CP) that have been treated in 14 hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the ELN recommendations. MR(4.5) was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction. All tests were performed at a central standardized according to ELN. Event-free-survival (EFS) was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Overall survival (OS) was measured from the start of imatinib until death of any cause or to the date patient was last known to be alive. RESULTS Data from 474 patients was analyzed. After a median observation time of 46 months, 5-year overall survival (OS) was 86%, 5-year event-free-survival was 53%. Of the 474 patients, 258 had adequate PCR evaluations during treatment. 118 of 258 (45,7%) patients achieved MR(4.5) and 69 of 258 (27%) had sustained response for at least two years after a minimum time of treatment of 3 years. The cumulative incidence of MR(4.5) after 9 years was 76% (median, 3 years). In the group that achieved MR(4.5), there was only 1 (0,8%) death and 1 (1,1%) progression compared to 8 deaths (5,7%) and 8 progressions (7,5%) in the group without MR(4.5); these differences were significant with p=0,03 and 0,02 respectively. In the subgroup of 69 patients that had had been treated with imatinib for 3 year or more and sustained deep response (RM4,5) for at least two years, 21 pts had low Sokal risk, 7 pts intermediate Sokal risk and only 4 pts a high Sokal risk. Unfortunately, in 37 pts the Sokal risk could not be accessed due to missing information. CONCLUSION In our series MR(4.5) is reached in the majority of patients with long-term imatinib treatment. MR(4.5) is a predictor of outcome with only one disease progression and one death due to CML in this group of patients. Unfortunatly PCR are not available for all patients in our clinical practice, but this situation are improving. Regarding the 69 patients with TKI discontinuation trial criteria, we find out that 21 patients fulfill such criteria. In the future, according to the results of current stop trials it could be possible include this selected group of CP CML patients in a prospective clinical trial. Disclosures No relevant conflicts of interest to declare.

scholarly journals Long-Term Outcome of Total Therapy Regimens: Impact of Molecular Subgroups

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3309-3309
Author(s):  
Frits van Rhee ◽  
Maurizio Zangari ◽  
Carolina D. Schinke ◽  
Guido J. Tricot ◽  
Doug Steward ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Low Risk ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Cure Fraction ◽  
Research Grant

Introduction. Our TT regimens for newly diagnosed multiple myeloma (MM) incorporate novel agents into a sequential treatment program comprising induction, tandem autologous stem cell transplantation and consolidation followed by 3 years of maintenance. Herein, we report the very long-term results in a large cohort of 1986 patients treated on successive TT protocols, the most mature of which (TT1, 2, and 3a) have a median follow-up ranging from 12.8 to 23.1 yrs. Methods. TT1 (1990) was followed by TT2 (1998), which introduced Thalidomide (T) in a randomized fashion. TT3 used bortezomib (V) throughout, with TT3a (2003) and 3b (2006) having different maintenance. TT3a used in year 1 of maintenance V, T and dexamethasone (D) and in years 2 and 3 TD. TT3b introduced lenalidomide (R) during maintenance for 3 years together with V and D. TT4 (2009) only enrolled patients with GEP-defined low risk disease and randomized patients to a standard arm or light arm using a similar regimen as TT3b. TT5 (2009) was specifically designed for patients who have a high 70-gene score and employed a dose dense treatment approach. Finally, TT6 (2009) accrued previously treated, patients irrespective of GEP-defined risk using a treatment schema similar to that used in TT5. Gene expression profiling was used to assign molecular classifications. These include HY (hyperdiploidy), LB (gene expression patterns frequently seen in patients with fewer focal bone lesions), MF (spikes in MAF and MAFB expression), MS (hyperactivation of MMSET +/- FGFR3), PR (over-expression of proliferation-related genes), and CD-1 or CD-2 (different forms of aberrant CCND1 and CCND3 expression). A mixed parametric cure model was used to estimate the proportion of patients with long-term, event-free survival, or the "cure fraction." When using progression free survival (PFS) in the model, the cure fraction is the percent of patients who are likely to never experience relapse based on trends in the survival times that have been observed. When using complete remission duration (CRD) in the model, the model estimates the cure fraction among patients who achieved complete response. Results. The median follow-up on the entire cohort patients was 11.6 years (range: 0.0-27.6) The median overall survival was 9.2 years, with 79.3% and 48.0% having an event-free survival greater than 3 and 10 years, respectively. Overall, patients with GEP70 low risk MM had estimated PFS and CRD cure fractions of 20.1% and 32.7%, respectively. GEP70 high risk MM patients fared much worse with estimated cure fractions of only 8.2 and 11.0%. The estimated PFS- and-CRD based cure fractions increased over time with successive protocols (PFS-cure: 6.0% in TT1 to 27.7% in TT4; CRD-cure: 9.3 to 49.8%). These cure fractions were consistent with the early plateau in the PFS and CRD curves seen at 9 years in TT4 patients. The highest cure fractions were seen in the CD-1 molecular group (34.9 and 40.3%) with intermediate outcomes in the HY (20.1 and 30.0%) and MS (22.8 and 33.5%) groups (Table 1). Surprisingly, low cure fractions were observed in the LB (1.1 and 13.5%) and CD-2 groups (13.5 and 26.4%). CD-1, LB and CD-2 groups had similar 5-yr PFS rates of 60, 60 and 63% respectively, but a steady low rate of relapse was observed in the CD-2 and especially the LB group. These findings were confirmed in a 5-yr landmark analysis showing high PFS and CRD cure fractions in the CD-1 group of 62.7 and 72.3% respectively contrasting to much lower cure fractions in the CD-2 (47.2 and 49.2%) and LB (30.8 and 45.0%) groups. Conclusions. We report excellent long-term outcomes in patients with GEP70 low risk MM and cure fractions in the range of 20-30%. Patients with LB and CD-2 subgroups have lower overall cure rates, despites similar initial 5-yr PFS rates compared to the superior performing CD-1 group, which can be explained by the occurrence of late relapses. Table 1 Disclosures van Rhee: EUSA: Consultancy; Adicet Bio: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Kite Pharma: Consultancy; Karyopharm Therapeutics: Consultancy; Castleman Disease Collaborative Network: Consultancy. Walker:Celgene: Research Funding. Davies:Janssen, Celgene: Other: Research Grant, Research Funding; Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. OffLabel Disclosure: anti-CD38 monoclonal antibody targeting myeloma

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