scholarly journals Intermittent Imatinib Mesylate in Children with Chronic Myeloid Leukemia: Results and Outcome

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4256-4256 ◽  
Author(s):  
Francesco Malaspina ◽  
Maria Caterina Putti ◽  
Michelina Santopietro ◽  
Saverio Ladogana ◽  
Rosamaria Mura ◽  
...  
Keyword(s):  
Side Effects ◽  
Board Of Directors ◽  
Pubertal Development ◽  
Advisory Board ◽  
Molecular Response ◽  
Advisory Committees ◽  
Group Iii ◽  
Group I

Abstract Imatinib mesylate (IM) has demonstrated to be highly effective in children with chronic myeloid leukemia (CML). The main issues remain the long-term side effects in pre-pubertal children and the poor compliance in adolescents. The aims of this study were: a) to evaluate the feasibility and efficacy of IM given intermittently to molecular responder (MR) CML children in chronic phase (CP), b) to reduce the long-term side effects of MR patients (pts) who started IM in pre-pubertal age, c) to improve compliance of poorly compliant adolescents in major MR (MMR). Among CP-CML pts aged <18 years at diagnosis treated with IM at a dose of 340 mg/m2/day and with a follow-up ≥36 months, those with a persistent MR4.5-MR5 or in MR with long-term side effects, and those in MMR who were poorly compliant to continuous IM, were considered eligible for an intermittent IM (int-IM) administration. The intermittent schedule consisted of IM administered at the same dose for 3 weeks monthly (3 weeks on, 1 week off). Quantitative molecular analysis of the BCR-ABL1 transcript levels was carried out monthly on peripheral blood and every 3 months on bone marrow, along with cytogenetics. Long-term side effects (bone and mineral metabolism, growth rate and pubertal development) were regularly monitored. Re-treatment with IM given continuously or with other tyrosine kinase inhibitors (TKI) was planned if there was a loss of MMR in two consecutive samples or a cytogenetic relapse. IM discontinuation was considered for patients with a persistent MR4.5-MR5. Fifteen of 58 CP-CML pts diagnosed between March 2001 and June 2015 received IM given intermittently for a median of 40 months(range: 14-86). Before starting int-IM, 5 pts had been in persistent MR4.5-MR5 for a median of 39 months (Group I), 4 pts had been in MR for a median of 28.5 months and had been suffering from long-term side effects (Group II), and 6 pts had been in MMR and were poorly compliant to treatment (Group III). Features and outcome of the 15 pts are shown in Table 1. Group I: 3/5 pts in MR4.5-MR5 discontinued int-IM after 16, 34 and 36 months and remain in continuous MR after 89, 90 and 107 months; 2 pts are still receiving int-IM for 14 and 36 months, respectively. Group II: 2/4 pts achieved a deeper MR (1 from MR4 to MR4.5 and 1 from MR4.5 to MR5) while on int-IM. However, 3 pts lost the response after 24 (cytogenetic relapse), 40 and 77 (molecular) months from the beginning of int-IM; all of them were successfully treated with IM given continuously. One pt is still receiving int-IM. Group III: 2/6 pts achieved a deeper MR (1 from MR3 to MR4.5 and 1 from MR3 to MR4) while on int-IM. However, 5/6 patients lost their response after a median time of 69 months (57-74). Four of them were treated with IM given continuously and 1 received dasatinib; all obtained a response. One, who achieved a deeper MR (MR3 to MR4), is still on int-IM after 86 months. Overall, 4/15 (26.7%) pts improved their molecular response while on int-IM and 3/15 pts (20%) successfully discontinued treatment. On the other hand, 8/15 pts (53.3%) failed int-IM after a median of 63 months (range 24-77) from the beginning (6 pts lost MMR and 2 pts had a cytogenetic relapse). No pt underwent a stem cell transplantation. Long-term side effects (bone metabolism, growth rate and pubertal development) progressively improved during IM given intermittently. At the last follow-up, 6 pts (4 MR5, 1 MR4.5, 1 MR3) are still receiving int-IM, 5 (3 MR4, 2 MR2) are receiving continuous IM, 3 (MR4.5-MR5) are treatment-free and 1 (MR3) is being treated with dasatinib. All patients are alive at a median time from diagnosis of 151 months (range 52-266). Our experience suggests that an intermittent schedule of IM given 3 weeks a month could be an effective strategy before stopping IM in CP-CML children in persistent deep MR. Moreover, this approach is capable of improving the molecular response in poor compliant pts and is useful to reduce IM-related long-term side effects. The relatively high number of relapses in group III (5/6, 83%) is indicative of its poor efficacy in pts not compliant to IM given continuously. Based on these data, a prospective cooperative study has been planned. Disclosures Malaspina: Sapienza University, Rome: Other: Resident in Hematology. Rizzo:Sapienza University, Rome: Other: Resident in Hematology. Locatelli:bluebird bio: Consultancy; Bellicum: 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; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Foà:CELGENE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; CELTRION: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau.

scholarly journals Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1589-1589
Author(s):  
Fabian Frontzek ◽  
Marita Ziepert ◽  
Maike Nickelsen ◽  
Bettina Altmann ◽  
Bertram Glass ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
High Dose ◽  
Advisory Committees ◽  
Scientific Advisory Board ◽  
Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

Excellent Outcome and Good Tolerability of Long-Term Imatinib in Patients with Chronic Myeloid Leukemia (CML)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2794-2794
Author(s):  
Simone Claudiani ◽  
Nikhita Gupta ◽  
Ji Soo Baik ◽  
Simona Deplano ◽  
Renuka Palanicawander ◽  
...  
Keyword(s):  
Side Effects ◽  
Adverse Events ◽  
Board Of Directors ◽  
Advisory Committees ◽  
Optimal Response ◽  
Time Points ◽  
The Future ◽  
Sokal Score

Abstract Introduction: The introduction of the tyrosine kinase inhibitors (TKIs) into clinical practice in the late 1990s has considerably improved both survival and quality of life for patients with CML. Imatinib was the only TKI available for several years with no useful drug treatment for patients with resistance and/or intolerance. Despite the lack of alternative agents the 8-year follow-up of the IRIS trialshowed that only 55% of patients were still on imatinib. The majority of those who discontinued did so for lack or loss of response rather than intolerance, suggesting that imatinib is very well tolerated in the long-term. This is particularly pertinent today as controversy persists as to the best agent for newly diagnosed patients. There is not only increasing evidence that the second and third generation TKIs are associated with more severe adverse events, but generic imatinib is now available in many countries at considerably less expense. We report our experience of treating 45 patients with continuous imatinib for more than 10 years. Methods: We interrogated our single centre database of all patients treated with TKIs for CML at our centre from June 2000 to March 2015. From a total of 832 patients we identified 188 CML who had received only imatinib. Of these, 45 patients had received treatment for more than 10 years. Results: The median duration of imatinib therapy was 6 years in the total cohort of imatinib only patients and 11 years (range 10-14.7) in the study group. All 45 patients were in chronic phase at diagnosis: the median age was 45.4 years (range 26-72). Forty patients were evaluable for Sokal scoring, with 19, 13 and 8 identified as low, intermediate and high risk respectively. The median imatinib starting dose was 400 mg daily. The proportions of patients who achieved optimal responses (OR), as defined by the ELN at 3, 6 and 12 months from start of imatinib, were 88.2%, 78.8 and 56.1% respectively. At 10 years the probabilities of CCyR, MR3, MR4, MR4,5 and MR5 were 100%, 100%, 100%, 100%, 75.6% respectively. The 10 year probability of obtaining a sustained (at least 2 years) molecular response was 100%, 64.4%, 35.6% and 15.6% for MR3, MR4, MR4.5 and MR5 respectively. In patients who were not optimal responders at one or more time points (n=21), the median dose of imatinib was ≥400 mg in the first 12 months of treatment; for 13/21 higher dosages (range 600-800 mg daily) were prescribed. We found a significant correlation between a low or intermediate Sokal score at diagnosis and OR at 3 months (p=0.012). No correlation was found between Sokal score and OR at 6 or 12 months. No statistically significant association was found between an optimal response at 6 or 12 months and the future depth of responses. In fact, the overall rates of sustained MR4.5 for patients optimal responders at 6 and 12 months were 52% and 52% versus 41.6% and 50% for non optimal responders at the same time points. Grade 4 toxicities and secondary malignancies were not observed during the follow-up. Seven pts (15.5%) experienced grade 3 events, including 1 each of supraventricular tachycardia and anemia, and neutropenia, fatigue and hypophosphataemia were each seen in 2 patients. The most frequent adverse event of any grade was fatigue (36% of pts), followed by anemia (27%) and neutropenia (18%). The cumulative probability of common side effects increased over the time. Cardiovascular events were mostly grade 1-2 palpitations and hypertension. At last follow-up, all pts were alive. Conclusions: Our patient cohort analysis confirms long term safety and tolerability of imatinib after 10 years of therapy. The majority of side effects were grade 1-2 and some increased in incidence over the time. The most frequent adverse events were hematological. Imatinib continues to provide an excellent therapeutic outcome granting deep molecular responses even in some patients deemed to be poor risk at diagnosis. ELN optimal response status at 6 and 12 months was not associated with prediction of the future depth of response, in this very good risk population (majority of patients in optimal response at 3 months). Disclosures Milojkovic: BMS: Honoraria; ARIAD Pharmaceuticals Inc.: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Apperley:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: 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, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Predictive Factors of Response and Survival of Lenalidomide and Rituximab As Initial Treatment of Follicular Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1533-1533 ◽  
Author(s):  
Paolo Strati ◽  
Ralph J. Johnson ◽  
Sheryl G Forbes ◽  
Loretta J. Nastoupil ◽  
Felipe Samaniego ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Initial Treatment ◽  
Research Funding ◽  
Advisory Board ◽  
Advanced Stage ◽  
Advisory Committees ◽  
Long Term Follow Up ◽  
Baseline Characteristics

Introduction. The combination of rituximab and lenalidomide (R2) is active in patients with untreated indolent lymphoma. Recent randomized trials (RELEVANCE) have demonstrated similar efficacy when compared to standard chemo-immunotherapy backbones. Long term follow up of patients receiving R2 as well as predictors of long term remission and survival have yet to be published. Methods. We prospectively evaluated patients with low grade advanced stage FL who received R2 as initial treatment at our institution between 07/2008 and 10/2014. Lenalidomide was given at 20 mg (day 1-21, in a 28 day cycle) for 6 cycles with rituximab monthly. Lenalidomide starting dose was 10 mg if baseline creatinine clearance was &lt; 60 mL/min. Patients with an objective response continued with 10-20 mg of lenalidomide with rituximab for up to 12 more cycles. Response was evaluated according to 2014 Lugano criteria. Results. One-hundred and one patients were included in the analysis, baseline characteristics are shown in the Table. Median number of provided cycles was 7 (range, 1-20). Median dose of lenalidomide was 20 mg (range, 5-20 mg), and 29 (29%) patients required a dose reduction. Fifty-six (55%) patients experienced grade 3-4 treatment-related toxicities, the most common (&gt; 5%) being neutropenia (39%), skin rash (20%), myalgia (16%) and fatigue (16%). Seven (7%) patients discontinued treatment before completion, after a median time of 4 months (range, 1-10 months): 4 because of toxicity (arterial thrombosis in 2, respiratory failure in 1, and skin rash in 1), and 3 because of progression. Ninety-eight patients were evaluable for response, while 3 patients discontinued treatment because of toxicity before first response assessment. Overall response rate was 98%, CR rate 90% (both achieved after a median of 6 months [range, 3-22 months]), and CR rate at 30 months (CR30) was 80%. Only female sex associated with a higher CR rate (96% vs 83%, p=0.05), while no baseline characteristic associated with CR30 rate. After a median follow-up of 88 months (95% confidence interval, 84-92 months), 31 (31%) patients progressed and/or died, 7-year progression-free survival (PFS) was 63%, and 13% of patients had a PFS &lt; 24 months (PFS24). Failure to achieve CR was the only factor associated with significantly decreased PFS (10 months vs not reached, p&lt;0.001) and higher likelihood of PFS24 (46% vs 5%, p&lt;0.001). No association was observed with baseline characteristics, including FLIPI and FLIPI-2 score. At most recent follow-up, transformation was reported in 3 (3%) patients, after 30, 32 and 42 months, respectively. Two (2%) patients have died, 1 of unrelated comorbid health conditions, 1 of progressive disease, and 7-year overall survival was 98%. Second cancers (excluding transformation) were diagnosed in 8 (8%) patients, after a median of 55 months (range, 3-105 months). These included: breast adenocarcinoma (2), melanoma (2), pancreatic adenocarcinoma (1), esophageal adenocarcinoma (1), and therapy-related acute myeloid leukemia. Discussion. Long-term follow-up show very favorable outcomes for patients with advanced stage FL receiving R2 as initial treatment, independent of traditional prognostic factors relevant to patients treated with chemoimmunotherapy, including FLIPI and FLIPI-2 score. Combination strategies, aimed at increasing depth of response to R2, may further improve outcomes observed with this regimen. Table. Disclosures Nastoupil: Bayer: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria. Westin:Janssen: Other: Advisory Board, Research Funding; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Genentech: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding. Wang:AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; MoreHealth: Consultancy, Equity Ownership; Acerta Pharma: Consultancy, Research Funding; BioInvent: Consultancy, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Juno Therapeutics: Research Funding; Dava Oncology: Honoraria; Celgene: Honoraria, Research Funding; Aviara: Research Funding; Kite Pharma: Consultancy, Research Funding; Guidepoint Global: Consultancy; VelosBio: Research Funding; Loxo Oncology: Research Funding. Neelapu:Pfizer: Consultancy; Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Allogene: Consultancy; Novartis: Consultancy; BMS: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Cellectis: Research Funding; Acerta: Research Funding; Karus: Research Funding; Poseida: Research Funding; Incyte: Consultancy; Cell Medica: Consultancy; Unum Therapeutics: Consultancy, Research Funding. Fowler:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: lenalidomide and rituximab are not yet FDA-approved as frontline treatment for patients with FL

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 ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 258-258 ◽  
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.

A Nationwide Observational Study of the Israeli Experience with Ponatinib Outside Clinical Trials in Chronic Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5155-5155
Author(s):  
Adi Shacham Abulafia ◽  
Pia Raanani ◽  
David Lavie ◽  
Yulia Volchek ◽  
Ron Ram ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Bone Marrow ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Response Rate ◽  
Advisory Board ◽  
Molecular Response ◽  
Advisory Committees

Abstract Ponatinib is an oral tyrosine kinase inhibitor (TKI) that has been designed to be effective also in patients who harbor the TKI-refractory threonine to isoleucine mutation at position 315 (T315I). In December 2014 the drug was granted an accelerated approval by the FDA, based on the promising results from the phase II PACE (Ponatinib Ph ALL and CML evaluation) trial. In this trial, 56% of previously treated patients who had resistance to or unacceptable side effects from dasatinib or nilotinib achieved a major cytogenetic response, including 70% of patients with the T315I mutation. Albeit the PACE trial convincingly demonstrated the efficacy of ponatinib, the wide use of the drug has been limited due to safety matters and in particular arterial thrombotic complications, reported in up to 17% of patients. Currently, there is very little real-life information regarding the use of ponatinib outside of clinical trials. The purpose of this study is to characterize patients with chronic myeloid leukemia (CML) who received ponatinib and to assess the effectiveness and safety profile of ponatinib outside of clinical trials. Between 4.2011 and 7.2015 (51 months) 24 patients with CML received ponatinib in 7 medical centers in Israel. We reviewed the medical records of these patients and asked their physicians to rank the quality of life of their patients on a 1 to 5 scale. Prior to ponatinib therapy, patients were treated for a median of 55 months (range: 1 to 215) with 1 to 3 different TKIs (median: 3). In addition 13 patients received at least one course of chemotherapy or interferon and 2 underwent allogeneic bone marrow transplantation. Screening for mutations at the DNA binding domain was performed at least once during the pre-ponatinib follow-up time in most patients (67%, N=16). Mutations were detected in 11 patients (69%) and the T315I mutation was detected in 8 of those. The median age when starting ponatinib was 44 years (rang: 23 to 79). Most patients had advanced disease and their disease was classified as either accelerated (21%, N=5) or blast crisis (41%, N=10) when they started ponatinib. Based on the medical history, 48% were at-risk to develop vascular complications either because of prior cerebrovascular event or myocardial infarction (18%) or because of vascular risk factors (30%). Baseline ECG and cardiac ECHO studies were available in 11 patients. Only two had signs of prior MI in ECG and none had significant structural or functional pathology. At time of analysis the median duration of follow up was 6 months (range <1 to 34 months), 4 patients died and 14 were still receiving ponatinib. Patients discontinued the treatment either because of major cardiovascular events (N=3), severe pancytopenia (N=1), planned bone-marrow transplantation (N=1) or because they were lost to follow-up (N=1). Seventeen patients were available for response assessment at time of analysis and the overall response rate was 77% (N=13). Five of six patients at chronic phase achieved either complete or major molecular response. Eight patients at accelerated phase or at blast crisis (8/11, 72%) achieved either hematological (5/11, 45%) or molecular response (3/11, 27%). Two of those, with hematological response, underwent allogeneic bone marrow transplantation. The median subjective scoring of ponatinib contribution to the quality of life of patients was 2.4 (range 1 to 5). Physicians that gave low scoring mentioned severe weakness, myalgia and cytopenias as a major concern. Conclusions: In real- life setting ponatinib is generally used as a last resort. In our cohort, it was almost exclusively given to patients who experienced failure to previous TKIs. The only exceptions were 2 patients who received ponatinib for suboptimal molecular response and achieved MMR when switched to ponatinib. Only one third of patients tolerated the recommended dose of 45mg. Yet, response rate was still relatively high, suggesting that a daily dose of 30mg might be appropriate. With only 6 months of follow-up we documented 3 cardiovascular events (12%) that prompted discontinuation of the drug and only one patient had a significant prior vascular risk. The high response rate and overall contribution to quality of life in patients with very few alternatives, who already experienced failure of other TKIs, support the use of this treatment for patients with advanced disease. Disclosures Raanani: Novartis: Other: Advisory Board, Research Funding; BMS: Other: Advisory Board; Ariad: Other: Advisory Board; Pfizer: Other: Advisory Board. Lavie:Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Rozovski:Novartis: Other: Advisory board.

scholarly journals Long-Term Outcome of Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib Front-Line

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-45
Author(s):  
Franck E Nicolini ◽  
Vincent Alcazer ◽  
Pascale Cony-Makhoul ◽  
Stephanie Dulucq ◽  
Sandrine Hayette ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Front Line ◽  
Advisory Committees ◽  
Long Term Outcome

Nilotinib (NIL) 600 mg daily has demonstrated its superiority over Imatinib 400 mg daily in terms of response and incidence of deep molecular response in the front-line chronic phase (CP) CML setting. In this observational study we have retrospectively analyzed the outcome of in- and out-study 202 patients (pts) treated in this setting with NIL 600 mg front-line, in "real-life" conditions. All pts with newly diagnosed adult CP-CML receiving NIL 300 mg BID alone front-line between 10/2007 and 06/2020, were eligible for this study. Data were retrospectively collected according to the current French regulations with pts' information. All pts were assessed and followed according to ELN recommendations 2003, 2006, and 2009 along treatment and to the recommendations from the French group of CML (D. Rea et al., Cancer 2018) in case of TFR. In this regard, a TKI was resumed if loss of MMR. All BCR-ABL1 assessments were performed in the 3 reference laboratories, standardised and expressed in % (IS) with ≥32,000 copies of ABL1 as control. The primary endpoints were the rate of molecular responses in the long-term and the (vascular) safety of Nilotinib. Secondary endpoints were the kinetics of molecular response, survival and safety of Nilotinib. Survival (OS, PFS & EFS) was defined according to ELN (J. Guilhot et al. Blood 2012). Two hundred and two patients were reported with 44% females and 56% males with a median age at diagnosis of 50.4 (17.5-83) years, and 26% of them had cardiovascular risk factors at onset (tobacco abuse 11%, hypercholesterolemia 9.3%, diabetes 1.45%, none with past history of cardiovascular events [CVE]). ELTS scores were high in 14%, intermediate in 31% and low in 55% of pts. Twenty-four (12%) pts harboured additional chromosomal abnormalities at diagnosis. The median follow-up after NIL initiation was 61.5 (1-147.5) months. At last follow-up 113 pts (55%) are not on NIL anymore for toxicities, TFR or resistance reasons. Twenty-eight (14%) pts present an arterial event on NIL (18% PAOD, 14% angina pectoralis, 7% myocardial infarction, 14% stroke, 47% others such as atrial fibrillation, cardiomyopathy...), that occurred after a median of 26 (0.6-98.5) months on NIL. Forty-six (22.5%) pts reached TFR criteria and stopped NIL after a median of 58.5 (27-126) months. The cumulative incidence (CI) rates of MMR at 1, 2 and 5 years were 64 (57-71)%, 79.4 (75.45-83.35)% and 95 (92-98.5)% respectively. For MR4, those were 35.5 (29-42)%, 60 (52-67)% and 82 (74.5-89)% respectively; and for MR4.5, were 14 (9-19)%, 31 (24-28)% and 62 (54-70.5)% respectively. The CI of sustained MR4.5 (i. e. patients eligible for TFR: MR4.5 ≥2 years) was observed in 30 (23-37)% at 3 years, 45.5 (36-55)% at 5 years and 52.5 (41.5-64)% at 6 years (Figure). The CI of patients entering TFR was 16.75 (10.5-23)% at 5 years and 51.94 (37.31-66.57)% at 10 years with a survival without MMR loss of 70.7 (58- 86)% at 1 year and 65.26 (50.6-84)% at 5 years. Nine (4.5%) pts progressed towards accelerated phase (4 pts) or BC (2 lymphoid, 3 myeloid) responsible for 5 deaths at latest follow-up. Among NIL resistant patients screened, 15 were harbouring ABL1 mutations (5 Y253H, 3 E255K, 3 T315I, 1 M244V, 1 G250E, 1 F359V, 1 V299L). Overall, 10 patients died (5 from CML, 5 from unrelated causes). The probability of OS was 95.75 [95%CI: 92.9-98.7]% at 2 years and 94.8 [91.5-98.3]% at 5 years, for PFS it was 94.92 [91.7-98.2]% at 2 years and 89.5 [84.7-94.6]% at 5 years, and EFS it was 78 [72.3-84]% at 2 years and 60.25 [53.3-68.1]% at 5 years. Regarding sustained MR4.5, univariate analysis showed that female gender (HR=2.46 [1.50-4.02], p&lt;0.001) and low ELTS (HR=0.41 [0.22-0.76], p&lt;0.004) had a significant impact, while multivariate analysis confirmed the role of these 2 factors (HR=2.31 [1.41- 3.79], p=0.001 and HR= 0.52 [0.30- 0.90], p=0.02) in addition to high ELTS (HR= 0.28 [0.14- 0.58], p&lt;0.001). Univariate and multivariate analyses demonstrated that only age impacted on the CI of CVE (HR= 1.07 [1.04-1.10], p&lt;0.001, and HR=1.07 [1.04-1.10], p&lt;0.001). NIL first-line efficiently limits progression of newly diagnosed CP-CML patients and provides high rates of sustained MR4.5, allowing TFR in a substantial proportion of pts. However, the onset of arterial occlusive events, especially in the elderly is a matter of concern in the choice of this compound at treatment initiation. Disclosures Nicolini: Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Sun Pharma Ltd: Consultancy. Cony-Makhoul:BMS: Speakers Bureau; Incyte Biosciences: Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy; BMS: Consultancy. Dulucq:Incyte: Speakers Bureau; Novartis: Speakers Bureau. Cayuela:Novartis: Speakers Bureau; Incyte: Speakers Bureau. Rea:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mahon:ARIAD: Honoraria; Pfizer: Honoraria; Novartis Pharma: Honoraria, Research Funding; BMS: Honoraria. Etienne:Pfizer: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau.

scholarly journals Second TKI Discontinuation in CML Patients That Failed First Discontinuation and Subsequently Regained Deep Molecular Response after TKI Re-Challenge

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 788-788 ◽  
Author(s):  
Thomas Pagliardini ◽  
Franck E. Nicolini ◽  
Stephane Giraudier ◽  
Philippe Rousselot ◽  
Gabriel Etienne ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Chronic Phase ◽  
Disease Free Survival ◽  
Molecular Response ◽  
Advisory Committees ◽  
Term Survival ◽  
Deep Molecular Response ◽  
Tki Discontinuation

Abstract Background: Tyrosine kinase inhibitors (TKIs) are able to induce, in some chronic myeloid leukemia (CML) patients, long-term undetectable molecular disease (UMD). Several studies have now demonstrated that TKIs could be safely discontinued in those patients previously treated with imatinib (STIM, TWISTER, EUROSKI) and more recently with nilotinib and dasatinib (STOP 2G-TKI). All these studies show a Treatment-Free Remission (TFR) rate reaching ~50%. However, a major issue needs to be resolved for the ~50% of patients that fail such TFR strategies. Methods: We have previously reported the possibility of a second imatinib discontinuation in 16 patients who obtained a second UMD state according to the STIM criteria (RE-STIM observational study, Legros et al. Blood 2012). Here, we report a larger cohort of patients who attempt twice TKI-discontinuations with enlarged inclusion criteria: Adults CML patients without prior allogeneic transplantation or progression to advanced phase CML undergoing a 2nd attempt of TKI discontinuation for sustained deep molecular response after a 1st failure. All patients were followed in CML reference centers and according to the EUTOS-ELN accreditation criteria for BCR-ABL assessments with minimal numbers of 32,000 ABL copies/sample. Results: At the time of analysis (1st July 2016), 67 patients (median age: 51 years (range: 25-80 years)) were included. At CML diagnosis, 64 patients were in chronic phase (CP) and 3 patients in accelerated phase (AP). The Sokal risk and the EUTOS long-term survival scores (ELTS) were respectively low in 47% and 68%, intermediate in 36% and 16%, high in 11% and 2% and unknown in 6% and 14% of patients. All patients were treated initially with imatinib and 16% of patients switch to nilotinib (6/11) or to dasatinib (5/11) for intolerance/resistance reasons prior to the 1st TKI discontinuation. The median time on TKI prior to the 1st discontinuation was 63 months (range: 30-146) and the median duration of 1st CMR was 35 months (range: 20-85). The 1st molecular relapse occurred with a median of 2.5 months (range: 0-22) and the second UMD after TKI re-challenge was obtained with a median of 4.4 months (0-40). The reason of the TKI re-challenge was loss of UMD in 43%, loss of MMR in 55% and unknown in 1%. The TKI re-challenge (imatinib 73%, nilotinib 16%, dasatinib 11%) was then administered during a median of 31 months (range: 9-72 months) before the 2nd attempt of discontinuation. At 2nd TKI cessation, 85% of patients were in UMD, 3% in MR4.5, 6 % in MR4, 3% in MMR and 3% unknown. Thirty out of sixty-eight (44%) patients remained treatment-free after a median follow-up of 21.5 months (1-106), see figure. Similarly to 1st attempts, the majority of loss of MMR occurred during the first 6-12 months in this 2nd attempt cohort. Gender, age, disease phase, prognosis scores, prior interferon exposure, initial TKI type, and duration of UMD were not found to have any impact on the outcome after the 2nd attempt in a multivariate analysis. In contrast, a longer time to obtain the first UMD before the 1st attempt was associated with a significantly lower molecular disease-free survival rate after the 2nd discontinuation (p = 0.048). All patients are alive at last follow-up except one who died from an unrelated CML reason (heart attack under imatinib). Conclusion: TKIs could safely and successfully be discontinued a second time in CML pts despite a 1st failure. Figure. Figure. Disclosures Nicolini: BMS: Consultancy, Honoraria; Ariad pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Etienne:BMS: Speakers Bureau; Pfizer: Speakers Bureau; ARIAD: Speakers Bureau; novartis: Consultancy, Speakers Bureau. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Guerci-Bresler:Pfizer: Consultancy; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; ARIAD: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Mahon:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ARIAD: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria.

Long Term Follow-Up After Imatinib Cessation For Patients Indeep Molecular Response: The Update Results Of The STIM1 Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 255-255 ◽  
Author(s):  
Francois-Xavier Mahon ◽  
Delphine Rea ◽  
Joelle Guilhot ◽  
Francois Guilhot ◽  
Françoise Huguet ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Prolonged Treatment ◽  
Molecular Response ◽  
Rt Pcr ◽  
Advisory Committees ◽  
Total Study Population ◽  
Long Term Follow Up ◽  
Analysis Point

Abstract Background Imatinib treatment significantly improves survival in patients with CML. We previously demonstrated that Imatinib could be safely discontinued in pts with deep molecular response (DMR) i.e., with undetectable minimal residual disease (UMRD) of at least 2 years (Lancet oncology, 2010;11: 1029-1035).Around 40% of CML patients with stable DMR on imatinib for at least 2 years are likely to remain in a prolonged treatment-free remission (TFR) after treatment is stopped and this rate has been safely confirmed by the recent Australasian TWISTER study (Blood, 2013; 122:515-22). Methods In this multicenter STIM study, imatinib (of >3 years duration) was prospectively discontinued in CML pts with who were in DMR with UMRD sustained for at least 2 years (ClinicalTrials.gov,NCT00478985). The UMRD was defined with a sensitivity> to 4.5 log with ≥ 50,000 ABL transcripts amplified as internal control). Importantly, the molecular relapse was defined as positivity of BCR–ABL transcript in quantitative RT-PCR confirmed by a second analysis point indicating the increase of one log in relation to the first analysis point, at two successive assessments, or loss of MMR at one point. Quantitative RT-PCR for BCR–ABL transcripts from peripheral blood was performed every month during the first year and every 2 months thereafter. Beyond 2 years, molecular biology FU was performed every 3 months.In cases of molecular relapse, the treating physician was recommended to reintroduce TKI treatment. Results From July 9, 2007, to Dec 17, 2009, 100 pts (48 male, 52 female) with CML (51 pts previously treated with IFN) and a median age of 63 years (range 29–80) were recruited in the STIM trial. Eight years after the first inclusion, the median follow-up of the STIM study is now 50 months (range 9-72) with a mean of 51 months. Sixty-one patients met the definition of molecular relapse: 58 relapses occurring during the first 7 months and 3 late relapses at month 19, 20 and 22, respectively). No other molecular relapse was observed at the last update (July 2013). However, 4 extra-hematological deaths were observed: 1 case in DMR after 9 months of imatinib cessation (due to myocardial infarction) and 3 cases belonging to the molecular relapse group (due to respectively stroke, mesothelioma, and gastric carcinoma). So, considering the death in DMR without any relapse (n = 1) as a competing event the cumulative incidence of molecular relapse remains 60%. Among the 58 patients alive, we confirmed that all patients were sensitive to TKI re-challenge, and were re-treated with imatinib (n=48), nilotinib (n=5) and dasatinib (n=5). One patient stopped again for side effects. A Second attempt of TKI discontinuation was proposed for 15 patients in sustained DMR and 5 cases of molecular relapse were reported at the last update after this second attempt of TKI cessation. Among the initial 38 patients alive who are still in DMR without any treatment the median follow up is 54 months (range : 24- 71).Taking into account the cost of imatinib and the number of months without treatment in the total study population at last analysis, the savings within the STIM trial were estimated at 5.5 millions Euros. Conclusion Imatinib can be safely discontinued in pts with a DMR of at least 2 years duration and we continue to recommend proposing discontinuation only in clinical trials with close molecular monitoring. In spite of the fact that we did not observed other molecular relapse beyond 2 years a long-term follow-up of the different cessation studies will be necessary to affirm cure. Because the life expectancy of de novo CML is now closed to the healthy population, the long-term medical costs and quality of life have become very important and depend on the possibility to cease safety TKI in long term. Disclosures: Rea: Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Etienne:novartis: Consultancy, 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; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Rousselot:BMS, Ariad, Pfizer: Honoraria from BMS, Ariad, Pfizer. Grants from BMS Other.

Prognostic Implication of Somatic Mutations By Next Generation Sequencing: An Analysis from the Mmrf Commpass Study in Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2079-2079
Author(s):  
Mattia D'Agostino ◽  
Stefania Oliva ◽  
Alessandra Larocca ◽  
Stefano Spada ◽  
Manuela Gambella ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Cox Model ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Group Iii ◽  
Mutational Status ◽  
Group I ◽  
Group Ii

Abstract Introduction: High throughput techniques, such as massively parallel sequencing, are becoming an attractive approach to characterize multiple myeloma (MM) genomic profiles. However, the clinical relevance and contribution to risk assessment of such approaches need to be established. The Multiple Myeloma Research Foundation (MMRF)CoMMpass trial (NCT01454297) has collected data from 1000 newly-diagnosed MM patients enrolled worldwide and observed through an expected follow-up of up to eight-years. Comprehensive analysis of somatic mutations detected in purified MM cells could reveal disease features with prognostic value, which may not have been detected using traditional approaches. Materials and methods: We analyzed data from the interim analysis 8 cohort. CD138+ purified MM specimens from bone marrow aspirates and mononuclear cells from peripheral blood were collected at diagnosis. Whole exome libraries from both tumor and constitutional DNA samples were created. Somatic single nucleotide variants (SNV) were identified using three different variant callers (Seurat,Strelka andMutect), only nonsynonymous SNV calls made from at least two callers were included in the analysis. Patients were analyzed on an intention-to-treat basis. We evaluated the impact on progression free survival (PFS) of recurrently mutated genes (with at least a nonsynonymous SNV in more than 10 patients) in a Cox model adjusted for international staging system (ISS) and cytogenetic profile (high risk, standard risk and missing). An additive score related to mutated genes was calculated on the basis the level of each coefficient estimated using a Cox Model with backward selection based on theAkaikeInformation Criterion (AIC). Results: 517 patients with baseline somatic mutation data were included in the analysis. Median age at diagnosis was 64 years (range 27-93). All patients received novel agents as first line treatment; 236 (45.6%) received autologous stem cell transplantation (ASCT). Each patient showed a median number of 55 nonsynonymous somatic SNV (range 8-1970) in a median number of 47 genes (range 5-1741). Excluding immunoglobulin genes, the most recurrent mutated genes were KRAS (25%), NRAS (19.5%), TTN (12.1%), MUC16 (9.1%) and DIS3 (9.1%). Based on the results of a multivariable Cox model corrected for ISS and cytogeneticprofile, we created a scoring system determined by the mutational status of 9 genes identified in a nonbiased manner (Table 1). Three groups were identified: group I (score 0-2, 17%); group II (score=3, 51%), and group III (score >3, 32%). After a median follow-up of 371 days, the 18-month PFS rate was 93% for group I, 85% for group II, and 67% for group III. In a Cox model adjusted for ISS and cytogeneticprofile, the hazard ratio was 2.34 (p=0.112) for group II versus group I, and 5.96 (p<0.001) for group III versus I. The prognostic trend of the score was confirmed in different patient subgroups including ASCT/no ASCT, standard/high risk cytogenetic profile, ISS I, II, or III. Of note, 23.3% of patients in group I had an ISS III and 30.4% of patients in group III had an ISS I. Conclusion: The use of a prognostic model based on the mutational status of 9 recurrently mutated genes could improve risk assessment of newly-diagnosed MM patients. To our knowledge, this is the largest study correlating nonsynonymous somatic SNV with MM patients' outcome. Longer follow-up and validation in independent cohorts are needed to confirm our findings. Disclosures Larocca: Amgen, Celgene, BMS, Janssen-Cilag: Honoraria. Gay:Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria.

Achievement and Maintenance Of Deeper Molecular Response By Switching To Nilotinib In Patients (pts) With Chronic Myeloid Leukemia In Chronic Phase (CML-CP) With Residual Disease On Long-Term Imatinib: ENESTcmr 36-Month Follow-Up

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 94-95
Author(s):  
Brian Leber ◽  
Francisco Cervantes ◽  
Nelson Spector ◽  
Jeffrey H. Lipton ◽  
Gabriel Etienne ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Molecular Response ◽  
Advisory Committees ◽  
Molecular Responses ◽  
Predictors Of Response ◽  
Equity Ownership

Abstract Introduction The 12- and 24-mo results of the Evaluating Nilotinib Efficacy and Safety in clinical Trials–complete molecular response (ENESTcmr) trial showed that pts with CML-CP with minimal residual disease after ≥ 2 y on imatinib achieved deeper molecular responses with switch to nilotinib. Results from ENESTcmr with 36-mo follow-up will be presented. Methods Pts with Philadelphia chromosome–positive (Ph+) CML-CP who had achieved complete cytogenetic response (CCyR) but had detectable BCR-ABL after ≥ 2 y on imatinib were included. Pts (N = 207) were randomized 1:1 to continue the same dose of imatinib (400 or 600 mg once daily [QD]; n = 103) or switch to nilotinib 400 mg twice daily (BID; n = 104). Rates of major molecular response (MMR; BCR-ABL ≤ 0.1% according to the International Scale [IS]) and MR4.5 (BCR-ABLIS ≤ 0.0032%) were evaluated by real-time quantitative polymerase chain reaction (RQ-PCR). Confirmed undetectable BCR-ABL was measured by RQ-PCR with a sensitivity of ≥ 4.5 logs, confirmed with a sensitivity of at least 4 logs in the next sample. Predictors of response were evaluated by multivariate logistic regression. Pts receiving imatinib were allowed to cross over to nilotinib if they had not achieved confirmed undetectable BCR-ABL by 24 mo or if they experienced treatment failure or confirmed loss of undetectable BCR-ABL at any time. Results By 24 mo, 77% of pts in the nilotinib arm and 91% in the imatinib arm remained on study treatment. Discontinuation rates were comparable between arms during year 2; 7% and 5% of pts discontinued study treatment in the nilotinib and imatinib arms, respectively, between years 1 and 2. Three pts crossed over to nilotinib before 24 mo; the no. of pts who crossed over at or after 24 mo will be presented. By 24 mo, more pts in the nilotinib arm achieved confirmed undetectable BCR-ABL compared with imatinib (22.1% vs 8.7%; P = .0087; Table). Regardless of molecular response at study start, more pts in the nilotinib arm than the imatinib arm achieved MR4.5 by 24 mo. None of the pts in the imatinib arm who lacked MMR at study start achieved confirmed MR4.5 or confirmed undetectable BCR-ABL by 24 mo (vs 20.8% and 16.7% in the nilotinib arm, respectively). Twice as many pts achieved and maintained MR4.5 in 3 consecutive assessments in the nilotinib vs imatinib arm (n = 12 vs 6). Age, sex, BCR-ABL level at study start, duration of prior imatinib (≤ 36 mo vs > 36 mo), and prior interferon were analyzed as predictors of response in univariate and multivariate analyses. None of these was clearly predictive of achieving MR4.5 or undetectable BCR-ABL in multivariate logistic regression. No cases of progression to accelerated phase/blast phase were observed with 24 mo follow-up. Three pts in the imatinib arm had confirmed loss of CCyR vs 0 in the nilotinib arm. Conclusions Switching to nilotinib continues to induce deeper molecular responses in pts with minimal residual disease on long-term imatinib therapy. More pts achieved confirmed undetectable BCR-ABL in the nilotinib arm vs the imatinib arm, with the difference between arms increasing between 12 and 24 mo and notably marked in pts lacking MMR at study start. Maintenance of deeper molecular responses achieved with nilotinib therapy may enable more pts to benefit from treatment-free remission trials. Disclosures: Leber: novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cervantes:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Spector:Novartis: Honoraria, 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. 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. Guerci-Bresler:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis : Honoraria, Membership on an entity’s Board of Directors or advisory committees; AMGEN: Honoraria. Forrest:Bristol Myers Squibb: Consultancy. Schwarer:Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Collins:Novartis: Employment. Szczudlo:Novartis: Employment, Equity Ownership. Hughes:Araid: Consultancy, Honoraria; Bristol Myers Squib: Consultancy, Honoraria, Research Funding; Novarits: Consultancy, Honoraria, Research Funding; CSL: Research Funding.

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