Impact of Additional Cytogenetic Abnormalities and Complex Karyotype on Event-Free Survival in Acute Promyelocytic Leukemia: Analysis from a Single Academic Center Plus the APML4 Study

Background: Current risk stratification for patients with acute promyelocytic leukemia (APL) is based solely on the presenting white blood cell count. There are conflicting data concerning the prognostic relevance of additional cytogenetic abnormalities (ACA) beyond t(15;17) and whether the presence of such abnormalities might influence treatment decisions for patients with APL. This is especially unclear among patients receiving ATO given that many existing data are from patients treated prior to incorporation of ATO into treatment paradigms. We sought to determine the prognostic importance of ACA and complex karyotype (CK) in influencing event-free survival in patients with APL. Methods: We analyzed patients with APL evaluated at our center since 2005 and patients treated in the Australasian Leukaemia and Lymphoma Group APML4 study (frontline ATRA + ATO + idarubicin,Lancet Haematology2015). We included all patients with baseline karyotype and those without karyotype but with FISH at diagnosis revealing ACA. Chart review extracted patient, disease, and clinical data. Only patients who commenced induction therapy with an ATO-based regimen were included in this analysis to ensure uniformity of the study population and applicability of results to contemporary clinical practice in APL. We also included patients deceased early in the disease course (<1 month). We excluded patients with absent follow-up information given our interest in relapse and patients who relapsed prior to transferring care to our center. We defined CK as the presence of >1 ACA beyond t(15;17). Coagulopathy was defined as either APTT/mean laboratory normal APTT >1.5, INR >1.5 (PT/mean laboratory normal PT >1.5 when INR and ISI unavailable), or fibrinogen <100 mg/dL. We defined events as either relapse or death. Associations between time-to event outcomes and patient and disease characteristics were assessed were calculated using univariate Cox proportional hazards models in each study separately. Fixed-effect meta analyses was used to combine estimates from both studies. Results: A total of 168 patients were included (N = 49 MSKCC, 109 APML4); 6 patients were removed from the MSKCC cohort due to relapse prior to initial visit and one from APML4 due to lack of follow-up information (Table 1). The mean age at diagnosis was 47 years in the MSKCC cohort and 43 years in the APML4. Median follow-up among survivors was 36 months (MSKCC, range 2-144) and 54 months (APML4, range 28-96); overall survival is displayed in Figure 1. Forty-nine (31%) patients' disease harbored ACA (most commonly trisomy 8 in 25 patients), and 17 CK (12% MSKCC, 10% APML4, denominator excludes one patient with single ACA by FISH). The event-free survival did not differ between ACA+ and ACA- (Table 2), but patients with +CK harbored inferior EFS (9/139 events non-CK vs. 4/17 events CK). No other clinical parameters that we queried correlated with EFS. Conclusions: In a large cohort pooled from a single-center experience and a cooperative prospective trial, the presence of an ACA beyond t(15;17) did not influence EFS in patients with APL. However, our data suggested that CK influences EFS. Further studies could collect data from other cooperative trials and/or single institutions to garner adequate power to better address the question of CK influencing EFS and confirm these preliminary findings. If a convincing signal emerges, treatment paradigms could be altered in the context of a prospective study (for example, intensifying or prolonging treatment) towards overcoming this adverse effect. Disclosures Park: Minverva:Consultancy;Kite:Consultancy, Research Funding;Amgen:Consultancy, Research Funding;Intellia:Consultancy;Artiva:Membership on an entity's Board of Directors or advisory committees;AstraZeneca:Consultancy;Incyte:Consultancy, Research Funding;GSK:Consultancy;Juno Therapeutics:Research Funding;Autolus:Consultancy, Research Funding;Genentech/Roche:Research Funding;Fate Therapeutics:Research Funding;Servier:Consultancy, Research Funding;Takeda:Consultancy, Research Funding;Novartis:Consultancy;Allogene:Consultancy.Stein:Biotheryx:Consultancy;Bayer:Research Funding;Genentech:Consultancy, Membership on an entity's Board of Directors or advisory committees;Syndax:Consultancy, Research Funding;Seattle Genetics:Consultancy;Abbvie:Consultancy;Amgen:Consultancy;Celgene Pharmaceuticals:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Agios Pharmaceuticals:Consultancy, Membership on an entity's Board of Directors or advisory committees;Astellas Pharmaceuticals: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, Research Funding;PTC Therapeutics:Membership on an entity's Board of Directors or advisory committees;Syros:Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.Tallman:Bioline rx:Membership on an entity's Board of Directors or advisory committees;Amgen:Research Funding;Rafael:Research Funding;Orsenix:Research Funding;ADC Therapeutics:Research Funding;BioSight:Membership on an entity's Board of Directors or advisory committees, Research Funding;Glycomimetics:Research Funding;Novartis:Membership on an entity's Board of Directors or advisory committees;Roche:Membership on an entity's Board of Directors or advisory committees;UpToDate:Patents & Royalties;KAHR:Membership on an entity's Board of Directors or advisory committees;Rigel:Membership on an entity's Board of Directors or advisory committees;Delta Fly Pharma:Membership on an entity's Board of Directors or advisory committees;Oncolyze:Membership on an entity's Board of Directors or advisory committees;Jazz Pharma:Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Membership on an entity's Board of Directors or advisory committees;Cellerant:Research Funding;Abbvie:Research Funding.

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

Blood ◽

10.1182/blood-2019-131870 ◽

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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Randomised Intergroup Trial of First line Treatment for young Low-Risk Patients (<61 years) with Diffuse Large B-Cell Non-Hodgkin's Lymphoma (DLBCL) with a CHOP-like Regimen with or without the Anti-CD20 Antibody Rituximab – 6-Year Follow-up of the Mint Study of the Mabthera International Trial (MInT) Group

Blood ◽

10.1182/blood.v116.21.111.111 ◽

2010 ◽

Vol 116 (21) ◽

pp. 111-111 ◽

Cited By ~ 1

Author(s):

Michael Pfreundschuh ◽

Evelyn Kuhnt ◽

Lorenz Trümper ◽

Anders Osterborg ◽

Marek Trneny ◽

...

Keyword(s):

Board Of Directors ◽

Survival Benefit ◽

Research Funding ◽

Good Prognosis ◽

Event Free Survival ◽

Advisory Committees ◽

Bulky Disease ◽

Free Survival ◽

To Receive

Abstract Abstract 111 Background: The addition of rituximab to CHOP-21 significantly improved clinical outcome in elderly patients with DLBCL (Coiffier et al., 2002). The MInT trial, randomized young good-prognosis patients to receive a CHOP-like regimen or the same CHOP-like regimen plus rituximab, and was stopped early because of superiority of the rituximab arm, and results were published with a median follow-up of 34 months (Pfreundschuh et al., Lancet Oncology 2006; 379-91). Objective: Because the MInT study was the first study to show a survival benefit with the addition of rituximab to a CHOP-like regimen in young good-prognosis patients, extended follow-up is important to determine whether the survival benefit is maintained over time and whether a definitive effect on cure rates can be shown. Methods: In a phase III intergroup study with participating cooperative groups from 18 countries, previously untreated patients (18-60 years) with low-risk DLBCL (age-adjusted IPI 0 or 1, stages II-IV and stage I with bulky disease) were randomized to receive 6 cycles of a CHOP-like regimen (CHEMO) or the same chemotherapy plus rituximab 375 mg/m2, given on day 1 of each 3-week regimen and on days 1, 22, 43, 64, 85 and 106 of the 2-week regimens, respectively (R-CHEMO). Radiotherapy (30-40 Gy) was planned to sites of initial bulky disease and/or extranodal involvement. The primary endpoint was event-free survival (EFS) with events defined as failure to achieve complete remission, progressive disease, relapse, death or additional therapy. The trial was powered to show a 10% difference in EFS rate after 3 years. Results: Between 05/2000 and 10/2003 a total of 823 patients were recruited of whom 396 were allocated to receive CHOP-21, 361 to CHOEP-21, 34 to MACOP-B, and 32 to PMitCEBO with or without rituximab. Toxicity, incidence of adverse events and severe adverse events in the CHEMO and the R-CHEMO arms were not significantly different. After a median follow-up of 70 (0.03-117) months, patients assigned to chemotherapy and rituximab had increased 6-year event-free survival compared with those assigned to chemotherapy alone (74.0% [95% CI 69.0–78.3] vs 55.7% [50.3-60.8]; log-rank p<0·0001), increased 6-year progression-free survival (79.9% [75.1 - 83.8%] vs 63.8% [58.2-68.8]; log-rank p<0.001) and increased overall survival (89.8% [86.0-92.6] vs 80.0% [75.3-83.9; log rank p=0.001). In a multivariate analysis event-free survival was affected by the addition of rituximab (hazard ratio [HR] 0.49, p< 0.001), age-adjusted IPI (HR 1.73, p<0.001), and bulky disease (HR 1.43, p=0.004). Similar effects were observed for OS, while PFS was affected by treatment arm (HR 0.49, p<0.001) and age-adjusted IPI (HR 1.8, p<0.001). As a consequence, a very favorable subgroup (aaIPI=0, no bulky) can be distinguished from a less favorable subgroup (aaIPI=1 and/or bulky disease) among good-prognosis patients treated with rituximab. There were 10 late (>60 months) events after CHEMO (61.4 to 96.1 months), including 4 in the very favorable subgroup, while all 8 late events (67.5 to 105.7 months) after R-CHEMO occurred in the less favorable subgroup only, and none in the very favorable subgroup. Conclusion: Addition of rituximab to a CHOP-like regimen leads to a significant improvement of the outcome in young patients with good-prognosis diffuse large B-cell lymphoma, with significant survival benefit maintained during a 6-year follow-up. However, except in the very favorable subgroup after R-CHEMO, late relapses after 5 years occur. While reduction of treatment in a randomized study like the FLYER trial of the DSHNHL is justified, further progress, e.g. by dose densification (UNFOLDER trial of the DSHNHL) and/ or dose escalation is still warranted for the less favorable subgroup. Supported by Roche, Deutsche Krebshilfe and KML. Disclosures: Pfreundschuh: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Trneny:Roche: Honoraria, Research Funding. Walewski:Roche: Honoraria, Research Funding. Pettengell:Roche: Honoraria. Jäger:Roche: Honoraria, Research Funding. Lopez-Guillermo:Roche: Consultancy.

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Seven Year Follow up and Comparison of Dosing Strategies from the Pivotal Phase II Clinical Trial of Lenalidomide Plus Rituximab (R2) in Previously Untreated Follicular Lymphoma

Blood ◽

10.1182/blood-2018-99-119592 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1594-1594

Author(s):

Nathan H. Fowler ◽

Preetesh Jain ◽

Loretta J. Nastoupil ◽

F. B. Hagemeister ◽

Sheryl G Forbes ◽

...

Keyword(s):

Clinical Trial ◽

Follicular Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Event Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Best Response

Abstract Introduction: We have previously reported the results of cohort A from a single arm, phase II clinical trial of lenalidomide with rituximab (R2) as frontline treatment for patients with previously untreated follicular lymphoma (FL), Fowler N et al Lancet Oncology 2014. Recent randomized studies (RELEVANCE) did not demonstrate superiority of either R2 or R-Chemo in untreated, high GELF FL, but follow up is short. We now report outcomes of an additional extended dosing cohort (12 mo of R2) and the long term follow up of the both dosing schedules in untreated FL. Methods: A total of 154 pts were included in the original clinical trial (FL, n=80; MZL, n=31; SLL, n=43). Characteristics were collected at the time of starting R2 treatment. Patients received lenalidomide 20 mg/day on days 1-21 of each 28-day cycle and rituximab 375 mg/m2 on day 1 of each cycle (6 cycles; schedule A) and lenalidomide 20 mg/day on days 1-21 of each 28-day cycle for cycles 1-6 then lenalidomide 10 mg/day on days 2-22 for cycles 7-12 with rituximab 375mg/m2 IV x1 weekly on cycle 1 and day 1 of every subsequent cycle (12 cycles; schedule B). Responders continued treatment for at least 6 but up to 12 cycles. The primary endpoint was overall response rate (ORR); secondary endpoints were complete and partial response (CR, PR), safety, and progression free survival (PFS). PFS was defined as time from starting treatment to disease progression or death, event free survival included time from starting treatment to discontinuation due to any cause and overall survival (OS) was defined from the time of initial diagnosis of FL to death/last follow up. Results: Eighty pts with FL were enrolled in study and followed a median of 86 months. Median age was 58 years (range, 29 to 84); 50% were males. 61% pts had grade 1 FL and 39% had grade 2 FL. Schedule A was administered in 50 pts and schedule B in 30 pts. Seventy seven pts were evaluable for initial response assessment and 76 (98%) responded. The best response rate was 95% (87% CR/CRu). At the time of last follow up, 23 patients experienced disease progression, 13 lost to follow up (all had CR as best response and had completed tx), 4 came off study due to pt choice/financial and 4 due to intolerance (2 arterio-thrombotic event, 1 respiratory failure, 1 intolerance) during therapy. After a median follow up of 86 mo, 23 pts (29%) progressed, 5 yr PFS was 75%. Five yr PFS was 70% and 82% for pts on cohort A vs B respectively (P=.30). Overall, 2 pts died, with a 5 year survival 97%, Figure-1 (A-B). The median event free survival in pts with FL was 85 months with a 5 year EFS of 59%. Subgroup analysis showed no statistically significant difference in PFS with FLIPI score, bulky disease and by initial bone marrow involvement. Pts who achieved CR had significantly longer PFS compared to those who did not achieve CR (not reached vs 78 months; p = 0.004), however the OS was not significantly different between the two groups Figure-1 (C-F). Grade 3 or 4 hematologic AEs included neutropenia (28%), thrombocytopenia (3%), and no anemia. Count recovery occurred in all pts with follow up and/or dose modification. Nine pts developed second primary cancers, including one melanoma in-situ, 3 localized skin cancers, and 2 secondary hematologic malignancies. Conclusions: A combination of lenalidomide with rituximab produced durable responses in pts with FL. At a follow up of 7 years, the majority of pts remain in remission and patients who achieved CR had the best outcomes. Five year PFS may be longer in pts who received 12mo of therapy, but will need larger analysis to confirm. Further studies are ongoing to analyze mutation dynamics and genomic profile to identify molecular biomarkers. Disclosures Fowler: Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Nastoupil:Novartis: Honoraria; Juno: Honoraria; Gilead: Honoraria; TG Therappeutics: Research Funding; Spectrum: Honoraria; Janssen: Research Funding; Merck: Honoraria, Research Funding; Karus: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Westin:Apotex: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Wang:Kite Pharma: Research Funding; Novartis: Research Funding; Pharmacyclics: Honoraria, Research Funding; Dava Oncology: Honoraria; Juno: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Acerta Pharma: Honoraria, Research Funding. Samaniego:ADC Therapeutics: Research Funding.

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Spirit 2: An NCRI Randomised Study Comparing Dasatinib with Imatinib in Patients with Newly Diagnosed CML

Blood ◽

10.1182/blood.v124.21.517.517 ◽

2014 ◽

Vol 124 (21) ◽

pp. 517-517 ◽

Cited By ~ 12

Author(s):

Stephen G O'Brien ◽

Corinne Hedgley ◽

Sarah Adams ◽

Letizia Foroni ◽

Jane F. Apperley ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Blast Crisis ◽

Cytogenetic Response ◽

Molecular Response ◽

Event Free Survival ◽

Advisory Committees ◽

Free Survival ◽

The Difference

Abstract Objective. SPIRIT 2 is the largest phase 3 prospective randomized open-label trial comparing imatinib 400mg with dasatinib 100mg daily: this is the first presentation of data comparing the two arms. Methods. 814 patients were recruited at 144 hospitals between August 2008 and March 2013. 812 started study medication (406 in each arm). The primary endpoint is event-free survival at 5 years. A key secondary endpoint is the rate of achievement of a BCR-ABL/ABL ratio of <0.1%IS (major molecular response (MMR), 3 log reduction or MR3). Results. Discontinuations. With a median follow up of 34 months a total of 289/812 (35.6%) patients have discontinued study medication. 118/812 (14.5%) patients have discontinued due to non-haematological toxicity: imatinib 47/406 (11.6%); dasatinib 71/406 (17.5%). 40 patients discontinued due to sub optimal response as assessed by the treating physician: imatinib 37/406 (9.1%); dasatinib 3/406 (0.7%). Side effects. Patients receiving imatinib experienced GI toxicity more often than patients receiving dasatinib; fatigue, rash and headache were more common with dasatinib. A higher rate of grade 3/4 thrombocytopenia was observed in the dasatinib arm: imatinib 17/406 (4.2%); dasatinib 52/406 (12.8%). Pleural effusions occurred in 78/406 (19.2%) patients on dasatinib; 13 of 78 (16.7%) patients required drainage. Arterial cardiovascular events (excluding hypertension) were experienced by 10/812 (1.2%) patients: imatinib 2/406 (0.5%; myocardial infarction (MI) x2); dasatinib 8/406 (2.0%; MI x1; angina/acute coronary syndrome x5; peripheral arterial disease x2). Hypertension was observed in 10/812 (1.2%) patients: imatinib 3/406 (0.7%); dasatinib 7/406 (1.7%). Venous CV events occurred in 7/812 (0.9%) patients: imatinib 3/406 (0.7%); dasatinib 4/406 (1.0%).Efficacy.For both PCR and cytogenetic analyses patients that had discontinued their allocated therapy or that did not have a 12 month sample were analysed as not having achieved MR3/CCR. The MR3 (PCR <0.1% IS) rate at 12 months in all treated patients is significantly different (p<0.001) between the two treatment arms: imatinib 173/406 (42.6%); dasatinib 236/406 (58.1%). The MR3 rate at 12 months in patients treated with dasatinib is 51/78 (65.4%) in those with a pleural effusion and 185/328 (56.4%) in those without (p=0.148, NS).The complete cytogenetic response (CCR) rate at 12 months is: imatinib 163/406 (40.1%); dasatinib 207/406 (51.0%). The difference between the two treatment arms is statistically significant (p=0.002) but caution is required in interpreting these data as there were missing analyses in 367 of 812 (45.2%) patients: imatinib 191 of 406 (47.0%), dasatinib 176 of 406 (43.3%). The difference in major cytogenetic response (MCR) rate between the two treatment arms at 12 months is not statistically significant: imatinib 200/406 (49.3%); dasatinib 218/406 (53.7%), p=0.206.Disease progression and deaths. 16 patients have progressed to either accelerated phase or blast crisis and 13 of those progressions were within the first year. Accelerated phase: imatinib 3/406 (0.7%); dasatinib 2/406 (0.5%). Blast crisis: imatinib 7/406 (1.7%); dasatinib 4/406 (1.0%). Conclusions. Dasatinib-treated patients have a higher rate of molecular response at 1 year but, with a median of 34 months follow up, there is no significant difference in rates of disease progression or overall survival. More patients abandoned imatinib than dasatinib due to investigator concerns about sub optimal responses. Further follow up is required to evaluate whether there will be differences in event free survival at five years. Disclosures O'Brien: Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Hedgley:BMS: Research Funding; ARIAD: Research Funding. Adams:BMS: Research Funding. Apperley:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Holyoake:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Byrne:BMS: Honoraria; Novartis: Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy. Osborne:ARIAD: Research Funding. Copland:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria. Clark:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Honoraria, Research Funding.

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Autologous Stem Cell Transplantation (ASCT) Versus Oral Melphalan and High-Dose Dexamethasone In Patients with AL (Primary) Amyloidosis: Long Term Follow-up of the French Multicentric Randomized Trial

Blood ◽

10.1182/blood.v116.21.1344.1344 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1344-1344 ◽

Cited By ~ 1

Author(s):

Arnaud Jaccard ◽

Veronique Leblond ◽

Bruno Royer ◽

Xavier Leleu ◽

Richard Delarue ◽

...

Keyword(s):

Board Of Directors ◽

Median Survival ◽

Research Funding ◽

High Dose ◽

Event Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Landmark Analysis ◽

To Receive

Abstract Abstract 1344 In September 2007 we published the results of a prospective randomized trial comparing in 100 AL amyloidosis patients, enrolled between January 2000 and January 2005, high dose melphalan with ASCT and the oral regimen M-Dex (melphalan 10 mg per square meter of body-surface area and dexamethasone 40 mg per day, on days 1 to 4). With a median follow-up of 3 years the median survival was better in the M-Dex arm (56.9 months) than in the ASCT arm (22.2) months (p=0.04). The hematological responses were not statistically different between the 2 arms and the higher toxicity of the ASCT arm was responsible for the shorter median survival. This study has been criticised because of the high treatment related mortality (TRM) in the ASCT arm but a landmark analysis of patients who survived for at least 6 months and who received their assigned treatment, did not show any difference in survival. A second frequent criticism was that too severe patients, who were not able to go through the high dose procedure, have been included. A separate analysis done within the 59 good risk patients showed a nonsignificant difference between the two groups in overall survival at 3 years (58% in the group assigned to receive ASCT vs. 80% in the group assigned to receive M-Dex; P = 0.13). A third concern was related to the duration of response, should high dose treatment, giving slightly more complete responses, results in more sustained responses and, with a prolonged follow-up, in a better long term survival ? To answer this question we extended the follow-up of the surviving patients. The new cut off date was August 1st, 2010, more than 5 and a half years after the last inclusion. Only 1 patient has been lost to follow-up. We did again the landmark analysis with the longer follow-up and we looked, in this population of 65 patients with 100% feasibility and 0 % TRM, at survival and remission duration. As the follow-up was very long and the biologic surveillance not planned after 2006 we took unequivocal events as censor points for the event-free survival analysis: deaths and second line treatment. At the first cutoff date, in 2006, 49 patients were alive, 30 in the M-Dex arm and 19 in the HDT arm. At the new cutoff date in 2010, 38 patients are alive, 22 in the M-Dex arm and 16 in the intensive arm, with a median follow-up of 49 months for the entire cohort and 86 months for surviving patients (figure 1). The majority of late deaths were amyloid related, but 3 patients in the M-Dex arm died of unrelated lung and digestive cancer. The median survival in the 2 arms has not been modified (56.9 month in the M-Dex arm and 22.2 month in ASCT arm, p=0.15). For the 65 patients included in the landmark analysis the median survival is not different in the 2 arms (103 month in the M-Dex arm and 97 month in ASCT arm) and the median event free survival is 56 months in the M-Dex arm and 26 months in the intensive arm (p=0.3, figure 2). Eleven surviving patients in the M-Dex arm and 6 in the intensive have not received a second treatment, 9 of these patients in the M-Dex arm and 5 in the ASCT arm have normal free light chain measurement at their last visit. Only 1 patient, assigned to receive ASCT, has been diagnosed with myelodysplasia. With a longer follow-up we did not found any superiority in the intensive arm in survival or remission duration even in the landmark analysis eliminating treatment related mortality. In the area of very efficient new drugs this analysis reinforces our choice to propose conventional treatment to amyloidosis patient avoiding the risk of intensive treatment.Figure 1.Survival according to treatment groupFigure 1. Survival according to treatment groupFigure 2.Event-Free Survival According to Treatment Group in the Landmark AnalysisFigure 2. Event-Free Survival According to Treatment Group in the Landmark Analysis Disclosures: Leblond: roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; mundipharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; genzyme: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees. Leleu:Celgene: Consultancy, Research Funding; Janssen Cilag: Consultancy, Research Funding; Leo Pharma: Consultancy; Amgen: Consultancy; Chugai: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

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Ponatinib and Chemotherapy in Young Adults with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Results of Ponalfil Clinical Trial after Completion of Recruitment

Blood ◽

10.1182/blood-2020-137489 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 29-30

Author(s):

Josep-Maria Ribera ◽

Olga García ◽

Pau Montesinos ◽

Pilar Martinez ◽

Jordi Esteve ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Molecular Response ◽

Event Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Allogeneic Hsct ◽

Central Artery

Background and objective. The combination of tyrosine kinase inhibitors (TKI) and chemotherapy (intensive, attenuated or minimal) has improved the prognosis of patients (pts) with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The combination of HyperCVAD and ponatinib has improved the molecular response and survival compared with other combinations of chemotherapy with first or second generation TKI (Jabbour E, et al, Lancet Haematol. 2018; 5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same induction and consolidation schedule of the ALL Ph08 trial (Ribera JM et al. Cancer 2019;125:2810-2817) The results of this trial after completed recruitment are herein reported. Patients and method. The PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin and prednisone) followed by consolidation (high-dose methotrexate, ARA-C, mercaptopurine, etoposide) and allogeneic HSCT. TKI use as maintenance was only scheduled for pts with persistence or reappearance of MRD. By July 2020 the 30 scheduled pts were recruited. The response to therapy (complete morphological [CR], molecular [complete, CMR or major, MMR] after induction and before allogeneic HSCT) (assessed by centralized BCR-ABL/ABL ratio),event-free survival (EFS), overall survival [OS]) and toxicity are herein analyzed. Results. Median age was 50 (20-59) years and 14/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score at diagnosis was <2 in 86% of pts. Median of WBC count was 6.4 (0.6-359.3) x109/L, Hb 90 (63-145) g/L, platelets 38 (11-206) x109/L. The immunologic phenotype was common in 26 cases, with molecular isoform p190 in 20 patients (67%), p210 in 9 (30%) and p230 in 1 (3%). CR was attained 26/26 patients (100%) (4 are still on induction therapy), with CMR in 11/26 cases (42%), MMR in 6/26 (23%) and no molecular response in 9/26 (35%)).Two patients withdrew the trial (thrombosis of the central retina artery and severe intestinal infection, one case each). Consolidation was given to 24 patients, 2/24 are receiving consolidation and 22 patients received allogeneic HSCT (14 in CMR, 6 in MMR, 2 without molecular response). No relapses before HSCT were detected. No transplant-related mortality was observed to date, but 1 patient withdrew the trial by severe GVHD. Ponatinib was given after HSCT in 4 pts due to loss of molecular response. Three pts relapsed after HSCT, one of them after documented loss of molecular response. All pts are alive (median follow-up of 4.5 months, range 0.5-26.2.2). The EFS probability at 30 months was 91% (79%, 100%) (Figure 1). One hundred and two adverse events (AE) have been registered in 20 patients, 25 of whom were severe (SAE) and occurred in 14 patients, prompting to withdrawn of the trial in 3 (thrombosis of the central artery of the retina, severe bowel infection, grade IV aGVHD, one case each). The most frequent AE were hematologic (26%), gastrointestinal (15%), infections (10%), hepatic (8%) and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina, one case each). Conclusions. The preliminary results of the PONALFIL trial after recruitment completed show a high short-term antileukemic efficacy with acceptable toxicity profile. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. Event free survival (EFS) of the whole series. Figure 1 Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Martinez-Lopez:Incyte: Consultancy, Research Funding; Novartis: Consultancy; BMS: Consultancy, Research Funding; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Garcia-Sanz:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Gilead: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Pharmacyclics: Honoraria; Takeda: Consultancy, Research Funding.

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ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Blood ◽

10.1182/blood-2019-128198 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1565-1565 ◽

Cited By ~ 1

Author(s):

Patrizia Mondello ◽

Irene Dogliotti ◽

Jan-Paul Bohn ◽

Federica Cavallo ◽

Simone Ferrero ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advanced Stage ◽

Advisory Committees ◽

Free Survival ◽

High Risk Patients ◽

Risk Patients

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with >90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= <0.001) in the ABVD group. Overall, the rate of severe toxicities was higher in the BEACOPPesc group in comparison with the ABVD cohort. In particular, there was a significant increased frequency of acute grade 3-4 hematologic adverse events (neutropenia 61% vs 24%; anemia 29% vs 4%; thrombocytopenia 29% vs 3%), febrile neutropenia (29% vs 3%), severe infections (18% vs 3%). Myeloid growth factors were administered to 85% and 59% of patients in the BEACOPPesc group compared to the ABVD group. Blood transfusions were required in 51% and 6% of patients in the BEACOPPesc group compared to the ABVD cohort. Progression during or shortly after treatment occurred in 5 patients in the BEACOPPesc group (4%) and in 16 patients in the ABVD group (6%; p= 0.62). Among the 96 patients who achieved a CR after BEACOPPesc and radiotherapy, 8 relapsed (8%), compared to 29 of 208 patients in the ABVD group (14%; p= 0.04). At a median follow-up period of 5 years, no statistical difference in progression free survival (PFS; p=0.11) and event-free survival (EFS; p=0.22) was observed between the BEACOPPesc and ABVD cohorts. Similarly, overall survival (OS) did not differ between the two groups (p=0.14). The baseline international prognostic score (IPS <3 vs ≥ 3) significantly influenced the EFS with an advantage for the high-risk group treated with BEACOPPesc (Figure 1A; p=0.03), but not the PFS (Figure 1B; p=0.06) and OS (Figure 1C; p=0.14). During the follow-up period, in the BEACOPPesc group one patient developed myelodysplasia and one acute leukemia. Second solid tumors developed in one patient in the ABVD group (lung cancer) and one in BEACOPPesc group (breast cancer). Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Maintaining Imatinib ≥600 Mg Daily in the First 12 Months of Chronic Phase CML Treatment Is Associated with Superior Event-Free Survival at 5 Years.

Blood ◽

10.1182/blood.v114.22.1125.1125 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1125-1125 ◽

Cited By ~ 1

Author(s):

Michael P Osborn ◽

Susan Branford ◽

Deborah L White ◽

John F Seymour ◽

Ruth Columbus ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Blast Crisis ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Event Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Event Rates

Abstract Abstract 1125 Poster Board I-147 The Australasian Leukaemia and Lymphoma Group conducted a trial (TIDEL I) in 103 patients with newly diagnosed chronic phase CML, using imatinib 600 mg/day with dose escalation to 800 mg/day for suboptimal response. This was defined as failure to achieve (1) complete haematological response (CHR) at 3 months, (2) major cytogenetic response (MCR) at 6 months, (3) complete cytogenetic response (CCR) or molecular equivalent at 9 months, or (4) less than 0.01% (IS) BCR-ABL by RQ-PCR at 12 months. Here we report the outcomes with all surviving patients having been treated for at least 60 months. We aimed to determine whether the patient outcome at 60 months was predicted by the molecular response within the first 18 months of imatinib therapy. The outcomes for patients maintaining a dose of imatinib of ≥600 mg/day in the first 12 months was compared to those who were on a reduced dose for at least part of this time. Event-free survival (EFS) was defined as death from any cause, accelerated phase/blast crisis (AP/BC), and loss of CHR, MCR or CCR. The 103 patients included 66 males and 37 females with a median (±SD) age of 49 (±14) years. All patients had an ECOG performance status of 0-2 at enrolment. The 5-year EFS was 71%, transformation (AP/BC) free survival (TFS) was 95%, and overall survival was 87%. Of the 14 patients who died, 3 died in blast crisis, 2 from transplant-related complications, 8 from CML-unrelated causes, and the cause of death of 1 patient was unavailable. The annual rates of progression to AP/BC over 5 years were 3%, 1%, 0%, 1%, and 0%, while annual event rates were 13%, 8%, 8%, 1%, and 4%. CCR was achieved by 89% of patients by 60 months, while 72% achieved a major molecular response (MMR) by this time. In the first 12 months of treatment, 55% of patients maintained an imatinib dose of ≥600 mg/day (mean ±SD dose = 604 ±10 mg/day), while 45% were on <600 mg/day for at least part of this time (mean ±SD dose = 511 ±100 mg/day). EFS at 60 months was significantly higher in patients taking ≥600 mg/day compared with those who had been dose-reduced to <600 mg/day (89% vs 56%, P<0.001). Annual event rates for the ≥600 mg/day group were 6%, 2%, 2%, 0%, and 2%, while annual event rates for those on <600 mg/day were 14%, 16%, 16%, 8%, and 4%. By 60 months, 96% of patients who had been on ≥600 mg/day within the first 12 months had achieved CCR, while only 80% of those who had been on <600 mg/day had achieved this milestone (P<0.001). Log rank analysis of the achievement of MMR was also significant (P=0.03). Overall survival and TFS after 12 months were both similar between the dosing groups. There was no difference between the dosing groups' median age (50 vs 48 years, P=0.36) or Sokal score (1.04 vs 0.94, P=0.33) that may otherwise account for these results. The outcome was also determined for all patients dependent on the BCR-ABL levels at various assessment timepoints. Patients with a BCR-ABL level of <10% (IS) at 6 months (n=92) had an EFS of 78% at 60 months, while all of those with a level >10% (IS) (n=8) had an event (P<0.001). Patients with a level of ≤1% (IS) at 12 months (equivalent to CCR) (n=81) had an EFS of 75% compared with 25% (n=13) for those with levels >1% (IS) (P<0.001). At 18 months, a level ≤0.1% (IS) (n=58) conferred an EFS of 88%, while those who had failed to attain this depth of response (n=30) had an EFS of 60%. There was a significant difference in EFS between those who had achieved an MMR at 18 months and those who had achieved a CCR, but no MMR (88% vs 67%, P=0.03). In conclusion, our data suggest that patients maintaining a dose of ≥600mg in the first 12 months of imatinib therapy are more likely to achieve CCR and MMR, and superior EFS compared to those with a lower dose. This study also confirms that achieving an MMR by 18 months is associated with improved EFS. This emphasises the value of achieving a molecular response early in the treatment course, as well as adding weight to the evidence supporting the role of molecular monitoring in CML. Disclosures Branford: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. White:Novartis and Britol-Myers Squibb: Research Funding. Seymour:Bayer Schering: Consultancy, Membership on an entity's Board of Directors or advisory committees, Travel grants; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Grants. Catalano:Roche: Honoraria, Research Funding, Travel grants. Mills:Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding.

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

Blood ◽

10.1182/blood.v116.21.207.207 ◽

2010 ◽

Vol 116 (21) ◽

pp. 207-207 ◽

Cited By ~ 18

Author(s):

Timothy P. Hughes ◽

Andreas Hochhaus ◽

Giuseppe Saglio ◽

Dong-Wook Kim ◽

Saengsuree Jootar ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Clonal Evolution ◽

Molecular Response ◽

Newly Diagnosed ◽

Advisory Committees ◽

Free Survival ◽

Superior Efficacy ◽

Rate Of Progression

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

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Observational Prospective Registry for the Assessment of the Clinical Impact of Starting Anti-Myeloma Treatment at Biological Relapse

Blood ◽

10.1182/blood.v124.21.4765.4765 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4765-4765

Author(s):

Adrian Alegre ◽

Merche Gironella ◽

Juan Miguel Bergua ◽

Esther Gonzalez ◽

Fernando Escalante ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Marrow Transplant ◽

Clinical Relapse ◽

First Line ◽

Advisory Committees ◽

Free Survival

Abstract Introduction: Despite the great medical advances associated with the introduction of thalidomide, bortezomib (BORT), and lenalidomide (LEN) for the treatment of multiple myeloma (MM), it remains an incurable disease. Most patients (pts) show disease progression, consistent with the clinical evolution of MM, and only a low percentage achieve long-term responses and extended progression-free survival (PFS). The heterogeneous nature of MM in both the clinical and biological setting is reflected in the heterogeneity of MM relapses. The International Myeloma Workshop Consensus Panel (Rajkumar, Blood 2011) states that treatment (Tx) shall begin either at clinical relapse with symptoms (clinR), or in the event of asymptomatic relapse with significant paraprotein relapse, biological relapse (BR). The purpose of this Spanish registry is to describe MM relapse patterns comparing the impact of Tx decisions in pts who meet the criteria for biological relapse (BR) according to IMWG criteria with those in whom Tx was delayed until clinical relapse (clinR). Here, the preliminary results of this study are presented. Methods: MM pts in (or previous to) first or second BR who have achieved ≥ PR since their last Tx are eligible for inclusion in this observational prospective registry at the time BR is detected. Evaluations performed at least bi-monthly are mandatory. A total of 41 Spanish sites participated in the registry following approval from their independent ethics committees, with 410 pts expected to be included, without physician’s decision of prescribing Tx affecting the inclusion. The main objective of the registry is to assess the time to progression (TTP) from the start of anti-MM Tx at the onset of asymptomatic BR vs. the start of Tx at the time of clinR. Secondary objectives are to describe demographics of BR; to assess the median time elapsing from BR to clinR; to assess overall response rate (ORR), event-free survival (EFS), PFS, overall survival (OS) at BR and at clinR (if appropriate); to asses safety and quality of life (QoL) using 2 validated questionnaires (European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 and QLQ-MY24); to document the tolerability profile of the Tx; and to describe the use of associated resources. Here, we summarize baseline characteristics and preliminary results from 83 pts (out of 126 registered pts) who had basal data in the registry at the time of this report. Results: Overall, 79% of pts presented with a BR and 21% were in a bi-monthly watchful waiting follow up. The mean age of pts was 67 years, 53% were female, 57% were in first relapse, 43% and 27% had an ECOG performance status (PS) of 0 and 1, respectively, while the ECOG PS was unknown in 30% of pts at the time of this report. In total, 30% of pts had ISS stage I, 26% had ISS stage II, and 22% had ISS stage III, while ISS stage data were not available or unknown for 12% and 10% of pts, respectively. MM types were IgG Κ (37% of pts), IgG λ (23%), IgA Κ (13%), IgA λ (9%), and type was unknown in 17% of pts. 28% of IgG/IgA MM types were Bence-Jones. Cytogenetic risk assessments were available in 66% of pts. Among those pts with a BR, 51% received active Tx without waiting for a ClinR. First-line Tx was BORT-based in 70% of pts. Overall, 55% of pts had undergone autologous stem cell transplantation, 15% had received consolidation Tx and 34% had received maintenance Tx. After first-line Tx, 17% of pts achieved a stringent complete response (sCR), 31% achieved a CR, 24% achieved a very good partial response (VGPR), and 10% achieved a PR. The median time to BR was 24.53 months. Most (63%) pts who registered after second relapse received LEN-based Tx. Conclusions: To our knowledge, this is the first prospective study in MM to evaluate BR as well as the effects of Tx based on the decision to start Tx at BR vs. clinR. In this preliminary cohort, the physicians’ decision to start active Tx at BR, before the onset of clinR in 50% of cases, was noteworthy. Further follow-up is needed to identify the differences between these two strategies. Updated clinical results will be presented at the meeting. MM-BR Study, Spanish Myeloma Group-GEM/PETHEMA Bibliography Alegre A, et al. Haematologica. 2002;87:609-14. Brioli A, et al. Blood. 2014;123:3414-9. Fernández de Larrea C, et al. Bone Marrow Transplant. 2014;49:223-7. Lenhoff S, et al. Haematologica. 2006;91:1228-33. Rajkumar SV, et al. Blood. 2011;117:4691-5. Zamarin D, et al. Bone Marrow Transplant. 2013;48:419-24. Disclosures Alegre: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lahuerta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ruiz:Celgene: Celgene Stock options as part of the employee's compensation plan Other, Employment. Vilanova:Celgene: Contracted by Celgene Other.

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