Very Long-Term Follow-up (> 80 months) of Imatinib (IM) First-Line for Chronic Phase (CP) CML Patients

Abstract Introduction Imatinib has indeed revolutionized the treatment of chronic myelogenous leukemia (CML) since more than 15 years now, especially in CP. The first patients (pts) in this setting were treated with this compound within the IRIS phase III trial from Novartis, started in January 2000. Regular updates of the results of this study have been presented during various meetings until year 7, and academic studies have recently reported the outcomes of IM first-line CP CML pts after 66 months follow-up. However, little is known about the very long-term outcomes (>8 years) of such first-line pts and these data might be of interest while generic forms of IM will be soon launched in this setting. In this study, we aimed to look at long-term outcomes in terms of efficacy and toxicities in first-line CP CML pts treated with branded form of IM (Glivec®). Methods This is a comprehensive retrospective analysis of first-line CP CML pts treated with IM first-line 400 mg daily since diagnosis and followed in 2 university reference centers for CML between 2000 and 2015, inside or outside academic or industrial clinical trials. All living pts have given their agreement for participation in this retrospective analysis. Pts have been analyzed in intention-to-treat, CML was defined according to ELN criteria [CP, accelerated phase (AP) and blast crises (BC)], Sokal, Euro and EUTOS scores have been calculated as published. Molecular biology tests have been performed according to ELN guidelines and BCR-ABL1/ABL1 were expressed as % on the international scale and 3 ELN conversion factors have been applied successively along time according to material exchanges performed with the central European laboratory in Mannheim. Cytogenetic and molecular responses have been defined according to the ELN criteria. Overall survival (OS) was calculated from the date of IM initiation until death at any time and for any reason; until progression to AP or BC at any time for progression-free survival (PFS); and until death, progression to AP or BC, failure on IM or IM treatment discontinuation for any cause including treatment-free remission (TFR), for event-free survival (EFS). The cut-off date for this analysis was the 20th of July 2,015. Results At time of analysis, 120 pts could be analyzed, with a median follow-up of 85.5 (1-194) months, 70 (58%) were males, with a median age of 55 (11-85) at IM initiation. Sokal score was high for 24(20%) pts, intermediate for 58 (49%), low for 34 (30.5%), unknown in 4 (0.5%) pts. Four (3.5%) pts had a variant Ph chromosome, 7 (6%) with additional chromosomal abnormalities, and 2 a masked Ph chromosome, 6 harbored atypical BCR-ABL1 transcripts excluded from analysis. Early molecular response (M3) was achieved in 86 (72%) pts, unreached in 20 (16%) pts, and unknown for 15 (12.5%) pts. It was predictive of Major Molecular Response (MMR) at 12 months (p=0.01, OR 5.35, 95%CI [1.3-31.94]), for MR4 rates at 24 months (p=0.03, OR 7.35 95%CI [1-328]) and for EFS (p=0.006) but not for OS and PFS in a multivariate Cox model analysis. MMR was achieved in 42% of evaluable pts at 12 months. Eutos, Euro and Sokal scores had no impact on OS, PFS and EFS. Five pts progressed to BC (1 myeloid, 4 lymphoid) within the 5 first years and died after allogeneic stem cell transplantation. The PFS rates were 97.5% at 2 years, 92% at 5 years, 88.6% at 10 and 14 years, EFS rates were 76% at 2 years, 60% at 5 years, 45% at 10 years and 21% at 14 years (figure 1), OS rates were 98% at 2 years, 95% at 5 years, 87% at 10 and 14 years. Figure 1: PFS and EFS in pts on IM first-line. (Dashed lines represent 95%CI). MR4.5 was achieved in 58 (48.5%) pts after a median of 46 (3-191) months and TFR strategy (or trial) was proposed in 28 pts (23.5%) and successful in 15 (12.5%) pts. At latest follow-up, after a median of 85.5 (4-180) months, 64 (53.5%) pts are still on IM, and 44 (37%) have switched to an alternative therapy for intolerance (17 pts, 14%) or resistance (16 pts, 13.5%, 7 with a BCR-ABL mutation) to IM and 11 for other causes (pregnancy, secondary tumors…). Overall, at latest follow-up, 10/120 pts died, 5 of CML progression and 5 from other causes. Conclusions After a very long median follow-up of more than 85 months, IM still consistently provides high rates of remission and survival, without disease progression and severe long-term toxicities. In addition, half of the pts reached the MR4.5 level, ≥2 years stable in 23.5% of the pts offering the possibility of a treatment-free strategy. Figure 1. Figure 1. Disclosures Nicolini: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mahon:Novartis: Consultancy, Honoraria; ARIAD: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria. Etienne:Novartis: Consultancy, Honoraria; BMS: Honoraria.

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Deep Molecular Response in Imatinib First-Line 418 Newly Diagnosed CP CML Patients.

Blood ◽

10.1182/blood-2018-99-113044 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3014-3014

Author(s):

Franck Emmanuel Nicolini ◽

Vincent Alcazer ◽

Pascale Cony-Makhoul ◽

Stephanie Dulucq ◽

Sandrine Hayette ◽

...

Keyword(s):

Board Of Directors ◽

Univariate Analysis ◽

Molecular Response ◽

Newly Diagnosed ◽

First Line ◽

Advisory Committees ◽

Free Survival ◽

Deep Molecular Response ◽

Chi2 Test

Abstract Introduction Deep molecular response (DMR) are now highly desirable goals in the treatment of CP-CML, especially in the front-line setting, because it can lead to a definitive treatment-free remission (TFR). However, such a goal is difficult to attain and does not concern the majority of patients (pts), but currently the precise number of pts able to access to TFR is unknown. Aims We aim to determine the number or newly diagnosed CP-CML pts reaching DMR, stable DMR, and access to TFR, on Imatinib (IM, Glivec®) first-line. Methods We retrospectively analyzed in an observational study, a cohort of newly diagnosed CP-CML pts treated with IM first-line 400 mg daily alone in our 3 reference centers between 2000→2018. All pts were followed according to the ELN recommendations 2006, 2010 and 2013. Clinical data were extracted from medical files, and responses (hematologic, cytogenetic, molecular) were analysed according to standard methods. Molecular results were standardised according to the ELN/Eutos programs since 2003, and were all expressed as BCR-ABLIS in %. DMR have been defined according to the ELN (NCP. Cross et al., Leukemia 2015). Stability of DMR has been defined as a stable if ≥2 years at least on 4 datapoints. TFR has been proposed to pts presenting the only current recommended criteria: MR4.5 ≥2 years at least on 4 datapoints [(Rea et al., Cancer 2018)], in the 3 centers involved, within clinical trials, pioneered in our country, or now as a clinical routine recommendation. Loss of MMR was the trigger for TKI resumption after IM cessation for TFR. Overall survival (OS), progression-free survival (PFS), failure-free survival (FFS, defined as progression to advanced phases death, loss of CHR, CCyR, or MMR, discontinuation of IM for toxicity, primary cytogenetic resistance) were analysed since IM initiation in intention-to-treat. Results Four hundred and eighteen pts have been included in this study, with a median age of 60.7 (48-70) years at diagnosis, with 57% males and 43% females. Sokal score (n=401) was low in 32%, intermediate in 51% and high in 17%. ACA were present at diagnosis in 5.5% of the pts (NA in 1.44%). Major BCR transcripts were found in 98% of pts, and atypical transcripts in 1.9%. CHR was reached in a median of 1 (0.85 to 1.64) month of IM, <10% BCR-ABL transcript (IS) level at 3 months was found in 81% of the pts, and only 9.5% of pts were in MMR at 3 months. The median follow-up after IM initiation is 77.4 (0.9-231.5) months, 125 (30%) pts have switched to TKI2 for IM resistance or intolerance. Overall, 252 (60%) pts reached MR4, 127 (30%) stable MR4, 170 (41%) MR4.5, and 82 (20%) stable MR4.5. The median time on TKI necessary for obtaining stable MR4.5 is 15.6 (5.9-28) months. The cumulative incidence of MR4.5 at 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months were 12.5%, 23.4%, 31.6%, 36.72%, 43.55%, 48.7%, 48.3%, 52.98%, 54.03%, 59.18% respectively (Figure 1A.). The cumulative incidence of stable MR4.5 at 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months were 5.76%, 11.5%, 17.83%, 21.82%, 26.35%, 28.13%, 28.13%, 29.13%, 29.13%, 29.13% respectively (See figure 1B.). Seventeen (13%) and 10 (12%) pts have switched IM→TKI2 before obtaining a stable MR4 and a stable MR4.5 respectively. Overall, 41 (10%) pts have reached the TFR criteria and stopped their TKI and 23 (56%) never lost their MMR after cessation, with a median follow-up of 41.7 (9.4-121.8) months. In an univariate analysis, only gender (female vs male, 39% vs 61% for no MR4.5 and 53.66% vs 46.34% for stable MR4.5, p=0.028, Pearson's CHI2 test), and MMR at 3 months (yes vs no, 3.74% vs 96.26% for no MR4.5 and 17.46% vs 82.54% for stable MR4.5, p<0.001, Pearson's CHI2 test) were identified variables impacting on stable MR4.5. A multivariate analysis could not be performed on so few discriminant factors identified in the univariate analysis. Conclusions Only 42 out 418 (10%) of the newly diagnosed CP-CML pts on IM first-line in our study reach the TFR criteria we recommended, and only 22 over 418 pts (5%)will finally definitively stop any TKI durably within the limits of this retrospective observational study. Urgent strategies in order to increase the access to definitive TFR are needed. Disclosures Nicolini: Sun Pharma Ltd: Consultancy; Incyte Biosciences: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Cony-Makhoul:BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; Incyte: Other: Travels for attending to Congress; Novartis: Consultancy, Other: Writing support, Travels for attending to Congress. Dulucq:BMS: Consultancy; Incyte: Consultancy. Hayette:Incyte: Consultancy. Mahon:BMS: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Incyte: Speakers Bureau. Etienne:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau.

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Frontline Treatment With Imatinib Mesylate in Chronic Myeloid Leukemia Patients in Early Chronic Phase: a Very Long-Term Analysis by the GIMEMA CML Working Party

Blood ◽

10.1182/blood.v122.21.258.258 ◽

2013 ◽

Vol 122 (21) ◽

pp. 258-258 ◽

Cited By ~ 2

Author(s):

Fausto Castagnetti ◽

Gabriele Gugliotta ◽

Massimo Breccia ◽

Giorgina Specchia ◽

Tamara Intermesoli ◽

...

Keyword(s):

Board Of Directors ◽

Chronic Phase ◽

Working Party ◽

Molecular Response ◽

Advisory Committees ◽

Term Outcome ◽

Long Term Outcome ◽

Free Survival

Abstract Background The chronic myeloid leukemia (CML) therapeutic scenario has been enriched by the approval of second generation TKIs as frontline treatment of early chronic phase (ECP) patients, but imatinib mesylate (IM) still represents the standard for many patients. The long term outcome is extremely important to assess the treatment efficacy and to decide on the allocation of resources. The phase 3 trials comparing second generation TKIs versus standard-dose IM have not still demonstrated a clear improvement in terms of progression-free survival and overall survival. In the IRIS trial, at 8 year, 55% of patients were still on IM and the overall survival (OS) was 85%. Other published reports have shorter follow-up. Aims and Methods To assess the very long-term outcome of CML patients treated frontline with IM, we analyzed 559 patients enrolled within 3 multicentric prospective studies conducted by the GIMEMA CML Working Party (NCT00514488, NCT00510926, observational trial CML023). Definitions: major molecular response (MMR), BCR-ABLIS ratio <0.1%; deep molecular response (MR4.0), detectable disease ≤ 0.01% BCR-ABLIS or undetectable disease with ≥10,000 ABL transcripts; progression, transformation to accelerated or blastic phase; failure, according to 2013 ELN criteria; event, treatment discontinuation for any reason or lost to follow-up. Information on survival and progression were regularly collected. All deaths, at any time and for any reason, were included. All the analysis have been made according to the intention-to-treat principle. Results Baseline demographics characteristics: median age: 52 years (extremes 18-84 years); male sex: 60%; high Sokal, high Euro and high EUTOS scores: 22%, 7% and 7%, respectively; clonal chromosomal abnormalities (CCA) in Ph+ cells: 4% (not evaluable in 32% of patients for insufficient number of metaphases); e13a2 BCR-ABL transcript: 36%. Median follow-up: 76 (7-99) months. The cumulative incidence of complete cytogenetic response (CCyR), MMR and MR4 was 88%, 85% and 61%, respectively. The median time to CCyR, MMR and MR4 was 6, 7 and 42 months, respectively. Patients with high Sokal, high Euro and high EUTOS scores had significantly lower overall estimated probability of CCyR and MMR with respect to low and intermediate risk patients. A high Sokal score also predicted a significantly inferior probability of MR4; patients with high Euro and high EUTOS score had lower overall estimated probability of MR4, but the difference were not statistically significant. The reasons for IM discontinuation were: lack of efficacy (19%), toxicity or death (9%), withdrawal of informed consent (3%); 4% of patients were lost to follow-up. The 8-year event-free survival (EFS), failure-free survival (FFS), progression-free survival (PFS) and OS were 55% (95% CI: 51-60%), 66% (95% CI: 61-70%), 84% (95% CI: 78-89%) and 85% (95% CI: 79-90%), respectively. A high Sokal and a high Euro scores were able to identify patients with significantly lower probability of EFS, FFS, PFS and OS with respect to the other patients. High EUTOS score patients had significantly poorer EFS and FFS, but PFS and OS differences were not significant. Age, performance status and e13a2 transcript resulted independent prognostic factors on PFS and OS. Conclusions Until now, the available data on the very long-term outcome of newly diagnosed chronic phase CML patients treated frontline with imatinib are limited to a company sponsored study (IRIS study). The GIMEMA CML Working Party provided an unbiased overview of the long-term imatinib therapeutic effects in a multicentric nationwide experience. These results should be taken into consideration to make treatment decision concerning the choice of the first line TKI, particularly in low risk patients. Acknowledgments University of Bologna, BolognaAIL, COFIN, Fondazione Carisbo. Disclosures: Castagnetti: Novartis Farma: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Gugliotta:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Abruzzese:BMS, Novartis: Consultancy. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; ARIAD: Consultancy. Cavo:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽

10.1182/blood-2019-128053 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4112-4112

Author(s):

Charline Moulin ◽

Romain Morizot ◽

Thomas Remen ◽

Hélène Augé ◽

Florian Bouclet ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Long Term Survivors ◽

First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

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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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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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Nilotinib Versus High-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses to Standard-Dose Imatinib: Updated Data From RE-Nice Study

Blood ◽

10.1182/blood.v120.21.3775.3775 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3775-3775 ◽

Cited By ~ 1

Author(s):

Soo-Young Choi ◽

Sung-Eun Lee ◽

Soo-Hyun Kim ◽

Eun-Jung Jang ◽

Jin-hwa Lee ◽

...

Keyword(s):

Dose Escalation ◽

Standard Dose ◽

Chronic Phase ◽

Cytogenetic Response ◽

High Dose ◽

Molecular Response ◽

Long Term Outcomes ◽

First Line

Abstract Abstract 3775 Background. In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In contrast, several clinical studies investigating the clinical implications of suboptimal response showed that patients with suboptimal responses tend to have poor long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this prospective study, we investigated whether switching to nilotinib (NIL) or high-dose IM may be more effective for patients with suboptimal molecular response to IM as first-line therapy. Methods. Early chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months (≤ 18 to ≥24 months) on first-line IM therapy at a daily dose of 400 mg were enrolled in this clinical trial, and informed consents were obtained from all patients. In NIL arm, patients received oral dose of 400 mg BID (800 mg/day) and in high-dose IM arm, patients received 800 mg/day administrated as 400 mg BID. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative MMR, MR4.0 and undetectable molecular residual disease (UMRD) rates during further 24 month follow-up. Safety profiles will also be assessed. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment. Results. With a data cut-off date of 10 Jul 2012, a total of 43 patients were randomized into NIL arm (n = 22) or high-dose IM arm (n = 21). With a median follow-up of 15 months (range, 1–36), all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL1 transcript levels was observed in all patients. Cumulative incidence (CI) of MMR by 12 months showed no significant difference between NIL arm and high-dose IM arm (37.8 ± 11.9% vs 34.8 ± 10.6%, P = 0.789). In NIL arm, 3 in 22 (14%) and 2 in 22 (9%) patients achieved MR4.0 and UMRD, respectively, and in high-dose IM arm, 1 in 21 (5%) patients achieved MR4.0. Overall, the patients treated with high-dose IM showed toxicities more frequently, such as fatigue, dyspnea and decreased phosphate. In addition, 10 patients in high-dose IM arm have cross-over to NIL treatment due to lack of response (n=9) and intolerance (n=1), and the median duration of NIL treatment was 14 months (range, 7–26 months). Among them, 5 (50%) patients have achieved MMR with a median NIL treatment duration of 12 months (range, 3–18). Conclusions. These results demonstrate that early switching to NIL or dose escalation of IM could be recommended, considering the results of standard dose of IM in suboptimal molecular responders. When the tolerability of treatment was considered for switching to NIL or high-dose IM, NIL may be preferred. Through further clinical investigation on a large patient population and longer period observation, the efficacy and safety of early intervention of suboptimal molecular response using NIL or dose escalation of IM will be needed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v122.21.92.92 ◽

2013 ◽

Vol 122 (21) ◽

pp. 92-92 ◽

Cited By ~ 27

Author(s):

Giuseppe Saglio ◽

Andreas Hochhaus ◽

Timothy P. Hughes ◽

Richard E. Clark ◽

Hirohisa Nakamae ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Eligibility Criterion ◽

Molecular Response ◽

Newly Diagnosed ◽

Long Term Outcomes ◽

Vascular Events ◽

Advisory Committees ◽

The Impact

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

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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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Real World Efficacy Evaluation of Branded and Copy Imatinib in Chronic Myeloid Leukemia: A Retrospective Multicentric Study from Argentina

Blood ◽

10.1182/blood-2020-137792 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Ana Ines Varela ◽

Georgina Bendek ◽

Carolina Pavlovsky ◽

Maria Josefina Freitas ◽

Veronica Ventriglia ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Molecular Response ◽

Advisory Committees ◽

Free Survival ◽

Safety And Efficacy ◽

Kaplan Meier ◽

Sokal Score

Background: Data on the safety and efficacy of copy drugs is usually unavailable. Imatinib mesylate is used to treat chronic myeloid leukemia (CML) patients in Argentina since 2002. During the last decade more than ten different imatinib copies are marketed by the different health-care systems in the country, usually for cost issues. In spite of the undoubted benefit of this tyrosine-kinase inhibitor indication in CML, there is no solid evidence that supports copy drug equivalent outcomes for this patient population. Aim: To compare the clinical presentation, treatment response and outcome of a chronic phase (CP) CML patient cohort treated with branded and copy imatinib in the real-life setting. Methods: Multicentric, retrospective trial based on data obtained from medical charts of adult CP CML patients treated with imatinib in 9 centers in Argentina from 2002 to 2020.We analyzed demographic characteristics and clinical characteristics described for branded and copy imatinib treated cohorts. Frequency of complete cytogenetic response (CCyR) at 12 months, Major molecular response or better(≥MMR) at 12, 18 and 24 months and overall MR4.0, MR4.5 and deep molecular response (MR4.0 +MR4.5 IS) were analyzed. Event was defined as failure, progression or CML related death. Kaplan Meier comparison of event free, progression free and overall survival. Statistics: IBM SPSS version 1. Results: A total of 568 CP CML adult patients (pt) treated with imatinib were included. Mean age at diagnosis: 45.7 years (range 18 - 85). Male 55.6% (316/568). Sokal Score was recorded in 471 pt: 57% (269/471) low, 26% (122/471) intermediate and 17% (80/471) high-risk. Median follow-up 107 months (RIQ: 36-149). Branded imatinib treatment 330 (58%) and imatinib copies 238 (42%). For branded and copy imatinib cohorts mean age 46,1 (18-85) and 45.3(18-80), male 53% (175/330) and 59% (141/238), median follow up 102 (RIQ 101-130) and 61 (RIQ 62-146) respectively. Sokal score low 58% (164/284) and 56% (105/187), intermediate 27% (77/284) and 24% (45/187) and high 15% (43/284) and19% (37/187). Frequency of CCyR at 12 months 71% (67/94) and 69% (41/59), ≥MMR at 12 months 57% (79/138) and 43% (39/89), ≥MMR 18m 66 % (61/92) and 71% (43/60), ≥MMR 24m 65% (96/147) and 79% (58/73). Overall MR4, MR 4.5 and Deep MR with branded imatinib 62.4% (186/298), 42% (118/276) and 63% (189/300), compared to 45(97/214), 24% (50/207) and 46% (99/215) with copies. Difference in evaluation throughout the treatment periods with loss of data did not allow response rate statistical comparison in predetermined timepoints. Kaplan Meier Event free survival median 229 months vs 75 months p 0.001, Progression free survival mean 318 months vs 208 pt 0.034 and Overall Survival mean 275 months vs 206 months for branded and copy imatinib respectively. Discussion: Several case reports have shown poor outcomes in patients treated with imatinib copy drugs, including loss of responses previously attained with branded imatinib. This study reports data from a large cohort of CP CML patients treated in daily practice during a long period of time. Treatment results at determined timepoints is comparable. Although management and treatment decisions were performed in different time periods, results show different outcomes in EFS and PFS between patients treated with branded vs copy imatinib. Overall survival in both cohorts is comparable. As studies assesing the safety and efficacy of the copy drugs compared with branded imatinib will hardly be performed this evidence calls for careful attention and strict follow up measures when managing CML patients with copy imatinib. Figure Disclosures Varela: Novartis: Consultancy, Speakers Bureau. Pavlovsky:Pint Pharma: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Freitas:Pfizer: Consultancy, Other: Advisory Board. Pavlovsky:Varifarma: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau. Moiraghi:Novartis: Speakers Bureau; BMS: Speakers Bureau.

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The BCR-ABL Transcript Levels At 3 and 6 Months Predict the Long-Term Outcome of Chronic Myeloid Leukemia Patients Treated Frontline with Imatinib Mesylate: A Gimema CML WP Analysis

Blood ◽

10.1182/blood.v120.21.1678.1678 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1678-1678

Author(s):

Fausto Castagnetti ◽

Gabriele Gugliotta ◽

Massimo Breccia ◽

Giorgina Specchia ◽

Elisabetta Abruzzese ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Roc Curves ◽

Molecular Response ◽

Advisory Committees ◽

Term Outcome ◽

Long Term Outcome ◽

Free Survival ◽

Transcript Levels

Abstract Abstract 1678 Background. Imatinib mesylate (IM) is the therapeutic standard for chronic myeloid leukemia (CML), but nilotinib and dasatinib, at least in selected patients, have the potential to replace it. The early prediction of poor outcome is important to optimize the treatment strategy. In IM-treated patients, BCR-ABL transcript levels according to the International Scale (IS) > 10% at 3 and > 1% at 6 months were able to identify high-risk groups (Marin et al, JClinOncol 2011; Hanfstein et al, Leukemia 2012). Similar analysis were performed within the IM arms of the ENESTnd trial (Hochhaus et al, EHA 2012) and the DASISION trial (Jabbour et al, EHA 2012). Methods. To investigate the prognostic impact of BCR-ABLIS levels at 3 and 6 months on the future response status and the long-term outcome of CML patients treated frontline with IM, we analyzed 559 patients enrolled within 3 trials of the GIMEMA CML WP (ClinTrialsGov NCT00514488/NCT00510926, observational trial CML023). Patients with evaluable QPCR sample at 3 and 6 months: 487/559 (87%) and 492/559 (88%), respectively. Definitions: major molecular response (MMR): BCR-ABLIS ratio <0.1%; molecular response with 4.0-log reduction (MR4.0): BCR-ABLIS <0.01%; failures: according to 2009 ELN recommendations. The rate of complete cytogenetic response (CCgR) and MMR at 1 year, the rate of MR4.0 at 2 years, the failure-free survival (FFS), the progression-free survival (PFS) and the overall survival (OS) according to the BCR-ABL transcript levels (≤10% vs >10 and ≤1% vs >1%) at 3 and 6 months were analyzed. Patients with events or censored within 3 or 6 months were excluded from the respective analysis. Receiver operating characteristic (ROC) curves were used for descriptive purposes. Results. Median age: 52 years (range 18–84). IM dose: 76% 400mg, 24% 800mg. Sokal score: 39% low, 39% intermediate, 22% high; EUTOS score: 93% low, 7% high. Median follow-up: 76 months (range: 7–99); 95% of patients had at least 5-year observation. BCR-ABLIS at 3 months: ≤1% in 336/487 (69%), >1% to ≤10% in 120/487 (25%) and >10% in 31/487 (6%). BCR-ABLIS at 6 months: ≤1% in 425/492 (86%), >1% to ≤10% in 54/492 (11%) and >10% in 13/492 (3%). Responses and outcomes according to transcript levels are presented in table 1. Patients with BCR-ABLIS >10% at 3 months achieved inferior CCgR and MMR rates at 1 year and inferior MR4.0 rate at 2 years, but the long-term outcome was comparable to patients with transcript levels < 10%. On the contrary, a BCR-ABLIS >1% at 3 months was associated, not only to lower subsequent response rates, but also to significantly inferior FFS, PFS and OS. The BCR-ABLIS levels able to predict for FFS, PFS and OS with maximal sensitivity and specificity (ROC curves) were 1.9%, 0.8% and 0.8%, respectively. Results were similar, with small differences, in the 6-month analysis. Conclusions. In a multicentric nationwide experience, the proportion of patients with BCR-ABLIS transcript levels >10% at 3 and 6 months was low. The risk distribution and the proportion of patients treated with high-dose IM may explain, at least in part, the differences with other published reports. At 3 and 6 months, a BCR-ABLIS cutoff of 1% was a reliable surrogate marker of response and outcome. A transcript level >10% identified a smaller cohort with inferior responses, but failed to predict the long-term outcome. A BCR-ABLIS level >1% at 3 and 6 months represents a warning, requiring a close monitoring. A switch to 2nd generation tyrosine kinase inhibitors should be considered. Acknowledgments. University of Bologna, BolognaAIL, COFIN, Fondazione Carisbo. Disclosures: Castagnetti: Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Novartis Pharma: Consultancy, Honoraria, Speakers Bureau. Gugliotta:Novartis: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria. Breccia:Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Abruzzese:Bristol Myers-Squibb and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavazzini:Novartis Pharma: Honoraria; Bristol Myers Squibb: Honoraria. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; ARIAD: Consultancy. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Martinelli:Bristol-Myers-Squibb: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Rosti:Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau.

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