scholarly journals Molecular Subtyping to Predict Risk of Venous Thromboembolism in Patients with Advanced Lung Adenocarcinoma: A Cohort Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3651-3651 ◽  
Author(s):  
Lorenzo Gervaso ◽  
Shyam K Poudel ◽  
Joanna Roopkumar ◽  
Chandana A Reddy ◽  
Nathan A Pennell ◽  
...  
Keyword(s):  
Overall Survival ◽  
Lung Adenocarcinoma ◽  
Board Of Directors ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Cleveland Clinic ◽  
Wild Type ◽  
Advisory Committees ◽  
Egfr Mutant

Background Venous thromboembolism (VTE) is a common complication in cancer care and can be predicted based on validated risk assessment tools. Innovative new therapeutics in non-small cell lung cancer (NSCLC) have changed practice patterns and mortality, and new predictors of VTE are therefore needed to better identify high risk patients in this setting. The incidence of VTE according to specific molecular subtypes of NSCLC has not been fully evaluated. The aim of this study was to evaluate rates of VTE in lung adenocarcinoma in relation to their molecular subtype and the association of VTE with survival. Methods We conducted a retrospective cohort study at Cleveland Clinic Taussig Cancer Institute, approved by the institutional review board. We identified advanced lung adenocarcinoma patients from 7/2002 through 07/2017 for whom molecular classification was available and treatment/follow-up was at the Cleveland Clinic. VTE diagnoses including deep-vein thrombosis (DVT) and pulmonary embolism (PE) were identified by electronic medical record review. Patients were classified according to their molecular subtype: wild-type, ALK-mutant or EFGR-mutant. VTE-free survival and overall survival (OS) rates for these categories were estimated by the Kaplan-Meier method and evaluated for association with VTE using Cox proportional hazard regression in each cohort. VTE was analyzed as a conditional, time-dependent covariate with respect to OS. Results The study population included 461 patients, 43.0% male, with a median age at diagnosis of 67 (range, 27-90) years. Of these, 157 (34.1%) were never-smokers. According to molecular subtypes, 165 patients were EGFR-mutant (35.8%), 46 (10.0%) ALK-mutant and 250 (54.2%) were wild-type. All patients had adenocarcinoma and 158 of 211 (74.9%) received a specific tyrosine kinase inhibitor according to their driver mutation. VTE occurred in 98/461 (21.3%) during a follow up of 33.1 months. Highest rates of VTE were observed in patients with ALK-mutant cancers (43.5%, N=20/46) followed by patients with EGFR-mutant cancers (21.2% N=35/165) and wild-type cancers (17.2%, N=43/250) (P < 0.05) (Figure 1). Cumulative rates of VTE at one year of follow-up were 20.7 % for ALK-mutant cancers, 11.1% for EGFR-mutant cancers, and 10.7% for wild-type cancers. The most common VTE event was DVT (49.0%, N=48/98) followed by PE (45.9%, N=45)). Overall survival was significantly worse in patients who experienced VTE in each molecular subgroup: ALK-mutant [HR 2.44 95% CI 1.03 - 5.79, p = 0.043], EGFR-mutant [HR 2.27 95% CI 1.43 - 3.59 p = 0.0005] and wild-type [HR 3.84 95% CI 2.67 - 5.52 p < 0.0001]) Conclusions VTE complicates more than one fifth of advanced lung adenocarcinoma patients. Nearly half of VTE events are PE. VTE is associated with worse survival across molecular subtypes. Patients with ALK-mutant advanced lung adenocarcinomas have the highest rates of VTE, exceeding those observed in patients with pancreas cancers and myeloma. These findings should be taken into consideration in decision-making regarding thromboprophylaxis. Figure 1 Disclosures Velcheti: Foundation Medicine: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Genentech: Consultancy; BMS: Consultancy; Reddy Labs: Consultancy; Alkermes: Consultancy; Boston Scientific: Consultancy; Merck: Consultancy. McCrae:Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Khorana:Janssen: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy.

scholarly journals Outcome of Autologous Stem Cell Transplantation in Waldenström's Macroglobulinemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2149-2149
Author(s):  
Romil Patel ◽  
Neeraj Y Saini ◽  
Ankur Varma ◽  
Omar Hasan ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Advisory Committees ◽  
First Remission ◽  
Relapsed Disease

Abstract Introduction: The role of autologous hematopoietic stem cell transplantation (auto-HCT) in the management of patients with Waldenström Macroglobulinemia (WM), a rare, indolent lymphoma, has not been established. We had previously published our experience with auto-HCT in a small cohort of WM patients1. Here, we present an updated analysis of auto-HCT with a larger cohort of WM patients. Methods and study population: The study cohort was comprised of 29 patients who underwent high-dose chemotherapy and auto-HCT at MD Anderson Cancer Center (MDACC). The Kaplan-Meier method was used to create survival curves. Overall survival (OS) was defined as the duration from date of transplant to death or last date of follow-up in living patients. Progression-free survival (PFS) was defined as the duration from date of transplant to either progressive disease or death, whichever occurred first. Results: Median age at auto-HCT was 60 (range, 43-75 years). Eight patients (28%) had concurrent light chain amyloidosis (AL). Of the five patients who had MYD88 testing completed, 3 were positive for the MYD88 mutation. Additionally, of these 3 patients, 2 were also positive for CXCR4 mutation. Patients received a median of 2 lines (range 1-6) of therapy prior to auto-HCT; 3(10%) patients had primary refractory disease, 8(28%) were in first remission, and 18 (62%) had relapsed disease. Median time from transplant to last follow-up for the surviving patients was 5.3 years. Preparative regimens received by the patients were: Melphalan (n=20), BEAM-R (n=2), Busulfan/Melphalan (n=1), Cyclophosphomaide/Etoposide/total body irradiation (n=1), Thiotepa/Busulfan/Cyclophosphamide (n=1), and Carmustine/Thiotepa (n=1). Three patients further went on to receive allogeneic transplant either after relapse from auto-HCT or due to disease transformation to aggressive lymphoma. Twenty-eight patients achieved engraftment with a median time to neutrophil engraftment of 11 days (range, 10-15 days). One patient suffered primary graft failure due to progression of disease and died 84 days after transplant. Non-relapse mortality was 3.4% at 1 year. All patients were eligible for response evaluation. The median OS from diagnosis was 12.2 years. Overall response rate was 96%: complete response (n=8, 27.6%), very good partial response (n=5, 17.3%), partial response (n=15, 51.7%), and progressive disease (n=1, 3.4%). PFS and OS at 5 years were 43.3% and 62.9%, respectively. Median PFS and OS from auto-HCT were 4.1 and 7.3 years (Fig. 1A). The median OS from auto-HCT in first remission + primary refractory and relapsed disease was 8.2 years and 4.1 years, respectively.16 patients were alive at the time of censoring while 13 patients had died. Causes of death include relapsed disease (n=6), secondary malignancy (n=2), infection (n=1), chronic graft-versus-host disease (n=1), and unknown (n=3). 8 patients (28%) were positive for concurrent AL amyloidosis. The sites of amyloid involvement were kidneys (n=2), lungs (n=1), bone marrow (n=1), heart(n=1), lymph nodes(n=1), gastrointestinal tract (n=1) and subcutaneous fat aspirate(n=5). The median overall survival for patients with amyloid involvement (n=8) was 12 years. On univariate analyses, the number of chemotherapy regimens prior to transplant (≤ 2 vs >2 lines) was the strongest predictor of overall survival (p=0.03, HR 0.3, CI: 0.09-0.9, log-rank) and PFS (p=0.001, HR 0.24, CI: 0.07-0.85, log-rank). The median PFS in patients with ≤ 2 lines and > 2 lines of therapy was 71 months versus 19 months, respectively (Fig. 1B). Conclusion: Auto-HCT is safe and feasible in selected patients with WM, with a high response rate and durable remission even in patients with relapsed or refractory disease. References: Krina Patel et.al. Autologous Stem Cell Transplantation in Waldenstrom's Macroglobulinemia. Blood 2012 120:4533; Disclosures Thomas: Celgene: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Array Pharma: Research Funding; Amgen Inc: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Takeda: Consultancy; Celgene: Consultancy; Spectrum Pharma: Research Funding; Janssen: Consultancy; Kite Pharma: Consultancy; Sanofi-Aventis: Consultancy; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

scholarly journals Minimal Residual Disease Eradication with Venetoclax in Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-14
Author(s):  
Alexander Coltoff ◽  
Joseph G. Jurcic ◽  
Peter Campbell ◽  
Daniel J. Lee ◽  
Mark L Heaney ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Median Overall Survival ◽  
Residual Disease ◽  
Institutional Research ◽  
Negative Group ◽  
Advisory Committees ◽  
Research Grants

Introduction The combination of the BCL-2 inhibitor venetoclax with an HMA (HMA/Ven) has improved outcomes in previously untreated patients with AML not eligible for intensive induction therapy. In a phase Ib study, 67% of patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) with a median overall survival (OS) of 17.5 months (DiNardo CD et al. Blood 2019; 133(1):7-17). HMA/Ven has also demonstrated efficacy in a heavily pretreated population with relapsed or refractory (R/R) AML, the majority of whom had prior HMA exposure (DiNardo CD et al. Am J Hematol 2018; 93(3):401-7). Measurable residual disease (MRD) is recognized as an independent prognostic indicator important for risk stratification and treatment planning (Schuurhuis GJ et al. Blood 2018; 131(12):1275-91). To date, however, there have been few reports on the effect of HMA/Ven on MRD. Methods This is a retrospective case series of patients with AML at a single-center tertiary-care institution. Patients ≥ 18 years of age who were treated with HMA/Ven between January 2017 and June 2020, either in the upfront or salvage setting, for AML were included. Outcomes included CR/CRi rate, MRD response, relapse free survival (RFS), and OS. MRD was assessed via multicolor flow cytometry with a sensitivity of 10-3 (0.1%). Results Nineteen patients were identified, 12 (63%) of whom were female. The median age at the time of HMA/Ven initiation was 71 years (range, 21 - 87 years). Ten (53%) patients had de novo AML and 9 had secondary or therapy-related AML. By 2017 ELN criteria, 3 (16%) patients had favorable-risk, 9 (47%) had intermediate-risk, and 7 (37%) had adverse-risk AML. Nine (47%) patients had R/R AML; 5 received HMA/Ven as first salvage therapy, and 4 as 2nd or greater salvage. Three (16%) patients had prior HMA exposure. No patient had prior venetoclax exposure. Median follow-up was 9.1 months (range, 1-21.1 months). Ten (53%) patients received azacitidine and 9 (47%) were given decitabine. Venetoclax doses ranged from 50 to 400 mg daily, depending on participation in a clinical trial and concomitant medications. Eight patients achieved a CR and 7 patients achieved a CRi for a combined CR/CRi rate of 79%. The CR/CRi rate was 90% (9/10) in the upfront setting, and 66% (6/9) in the salvage setting. The median time and number of cycles to best clinical response was 2.3 months (range, 0.9-3.9 months) and 2 (range, 1-3 cycles), respectively. Eleven (73%) of the 15 responders achieved MRD clearance after a median of 2 cycles (range, 1-3 cycles) (Table 1). Two of 4 (50%) MRD-positive patients relapsed, while 4 (36%) of 11 MRD-negative patients relapsed (Figure 1). Relapse occurred at a median of 2.0 months (range, 1.3-2.7 months) in the MRD positive group and 11.0 months (range, 2.8-14 months) in the MRD negative group. One patient died of infectious complications while MRD negative. Three patients, all of whom were treated for R/R disease, proceeded to an allogeneic stem cell transplant (HSCT). Two were MRD negative at the time of HSCT and all remained in remission. At the time of data cutoff, 7 (64%) of 11 MRD-negative patients were alive, and all 4 MRD-positive patients were alive. Causes of death in the MRD-negative group included disease relapse (3 patients) and infection (1 patient). Median overall survival in the entire cohort (range, 32 days-NR) was not reached. Conclusions HMA/Ven was highly effective as both upfront and salvage therapy. Surprisingly, the salvage CR/CRi rate in this series was 66%, allowing half of the responders to proceed to HSCT. The majority (73%) of responders achieved MRD negativity. While MRD status influenced RFS, 36% of MRD-negative patients relapsed. Additionally, the same percentage of MRD-negative patients died during follow-up, versus none of the patients with MRD-positivity. This indicates the need for more sensitive methods to assess MRD and for novel therapeutic strategies to eliminate MRD, thereby improving long-term outcomes. Larger prospective studies are needed to define the role of MRD assessment with venetoclax-containing regimens. Disclosures Jurcic: AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Syros Pharmaceuticals:Research Funding;PTC Therapeutics:Research Funding;Arog Pharmaceuticals:Research Funding;Kura Oncology:Research Funding;Forma Therapeutics:Research Funding;Astellas:Research Funding;Genentech:Research Funding;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS:Consultancy, Research Funding.Campbell:AstraZeneca:Consultancy.Lee:Genentech:Research Funding;Sumitomo Dainippon Pharma Oncology, Inc.:Research Funding;AbbVie:Research Funding;Novartis:Research Funding;Bayer:Research Funding;Celgene:Consultancy;Forty Seven:Research Funding.Heaney:Blueprint Medicines Corporation:Research Funding;BMS:Research Funding;CTI Biopharma:Consultancy, Research Funding;Deciphera:Research Funding;Incyte:Research Funding;Novartis:Consultancy, Research Funding;Sierra Oncology:Research Funding;AbbVie:Consultancy;Partner Therapeutics:Consultancy.Lamanna:Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Octapharma:Research Funding;Juno:Other: Institutional research grants, Research Funding;Gilead:Consultancy, Membership on an entity's Board of Directors or advisory committees;Astra Zeneca:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Pharmacyclics:Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Bei-Gene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Abbvie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Oncternal, Verastem, TG Therapeutics:Other: Institutional research grants, Research Funding;MingSight:Other: Institutional research grants, Research Funding;Loxo:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Columbia University Medical Center:Current Employment.

Effectiveness of Reduced Toxicity Conditioning Regimen with Intravenous Busulfan Plus Pentostatin (BUPENT) in Patients Older Than 50 Years with Advanced Hematologic Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3331-3331
Author(s):  
Tulio E. Rodriguez ◽  
Mala Parthasarathy ◽  
Scott E. Smith ◽  
David H. Vesole ◽  
Zachary M. Earley ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Graft Failure ◽  
Conditioning Regimen ◽  
Advisory Committees ◽  
Reduced Toxicity

Abstract Abstract 3331 Poster Board III-219 Introduction Current data suggests that recipient age above 50 is associated with an inferior outcome after myeloablative allogeneic stem cell transplantation (SCT). Overall survival (OS) of 31%, and transplant related mortality (TRM) of 17% at 100 days have been reported in this population (Ditchkowski, et al 2005; Yanada, et al. 2004). Encouraging results are observed with non-myeloablative conditioning regimens. However, for patients with a high relapse risk, this approach may not be sufficient to achieve long term disease control. In these cases, a reduced toxicity, yet ablative stem cell transplantation (RT-SCT) may give adequate time to the transplanted cells to mature and mount an immune-mediated antitumor response. This study evaluated the outcome after RT-SCT using a conditioning regimen consisting of intravenous busulfan (Bu) and pentostatin (Pent). Methods Consented adult patients up to 70 years with a fully-matched related (MRD) or unrelated donor (MUD) were screened for enrollment. Conditioning consisted of Bu 1.6 mg/kg every 12 hours days -7 to -4, and Pent 4 mg/m2 on day -3 and -2 prior to stem cell infusion on day 0. GVHD prophylaxis was methotrexate 10 mg/m2 on day 1, and 5 mg/m2 on days 3, and 6. Tacrolimus was started on day -2, and then tapered over 1 month after day +100. Characteristics Twenty six patients were analyzed. Male to female ratio was 1:1. Stem cell source was from MRD in 15 patients and MUD in 11. Median age was 62, with 92% of patients being older than 50 years. Indications for treatment were AML (35%), MDS (42%), Refractory CLL (23%), Relapsed NHL (12%), and Philadelphia (+) ALL (4%). All AML patients were high risk either due to poor cytogenetic, transformation, or relapse and only two of them were transplanted in first complete remission. MDS patients were RAEB (36%), secondary MDS (36%), or multilineage dysplasia (18%). Two patients had prior autologous transplants. Results No graft failure was observed. All patients achieved neutrophil (NEU) engraftment. Two patients expired prior to platelet (PLT) engraftment. Median engraftment days for NEU and PLT were 13 days. At a median follow up of 25 months, the OS and progression free survival for the entire group was 40% and 38% respectively. The OS in the MRD group was 58%. TRM at 100 days was seen in one patient (4%) due to veno-occlusive disease (VOD). Limited chronic GVHD was the most common observed toxicity (54%), followed by diarrhea (30%) and mucositis (23%). Mucositis was mainly grade 1 (8%) and grade 2 (8%). No grade 3 mucositis was observed. There was only one case of VOD and one case of acute GVHD. Conclusion To our knowledge, this is the first report of a RT-SCT using BuPent. This study demonstrates the efficacy of the regimen in patients older than 50 years. No graft failure was observed and the regimen related toxicity was acceptable in this high-risk population. The overall survival of 40% at a median follow up of 25 months compares favorably with prior reports of myeloablative allogeneic stem cell transplatation in patients older than 50 years. This regimen provides an exciting opportunity to extend the benefits of allogenic transplant to an older population, and warrants replication with larger controlled trials. Disclosures Rodriguez: Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vesole:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Millenium: Speakers Bureau; Centocor Ortho Biotech: Speakers Bureau.

Long-Term Clinical Outcome of Patients with Acquired Aplastic Anemia In Brazil Using Cyclosporine-A (CSA) and Prednisone (PRED): 20 Years Follow-up From a Single Institution

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2234-2234
Author(s):  
Larissa A Medeiros ◽  
Samir K Nabhan ◽  
Marco Antonio Bitencourt ◽  
Michel M. Oliveira ◽  
Vaneuza A M Funke ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Overall Survival ◽  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Board Of Directors ◽  
Clonal Evolution ◽  
Severe Aplastic Anemia ◽  
Advisory Committees

Abstract Abstract 2234 Introduction/Background: Immunosuppressive therapy is the best alternative for patients with severe aplastic anemia (SAA) without matched sibling donor or with age > 40 years. Since 1988, an alternative protocol was developed with cyclosporine (CSA) and prednisone (PRED) due to irregularity in distribution of anti-thymocyte globulin (ATG) in Brazil. This study aims to show the results of this treatment on the quality of response, overall survival and development of clonal evolution. Materials and methods: 384 patients diagnosed with SAA (Camitta and Bacigalupo criteria) were evaluable by medical records review from 12/1988 to 12/2008. The immunosuppressive therapy consisted of CSA: 12mg/kg/day BID from day (D)1- D8, then 7mg/kg/day BID until 1 year. After that CSA was progressively tapered (5% each month) and ultimately stopped usually by two years. CSA levels were kept between 200–400ng/ml. PRED: 2mg/kg/day from D1-D14 then 1mg/kg/day from D15- D45. From that day on PRED dose was tapered 20% each week. Sulfamethoxazole-trimethoprim and fluconazole were used for prophylaxis against Pneumocystis jiroveci (P carinni) and fungal diseases, respectively. Treatment response was defined as Table 1. Treatment evaluation was performed at 6 weeks, 3, 6 and 12 months and then yearly. At diagnosis: median age was 21 years (2-75), disease duration 95 days (2-4749), and median number of transfusions were 12 (0-200). Etiology was idiopathic in 78%. In peripheral blood, median hemoglobin was 7.4g/dL, granulocytes 580/uL, platelets 12.000/uL and reticulocyte 0.5% (corrected value). 60% of the patients had not been treated previously. Results: Overall survival was 61% ± 3 with a median follow-up of 7 years (range: 2 months - 23 years). Response to treatment: 51% had some degree of response, with good quality of life and transfusions independent (143 patients with complete response and 53 partial response). 36 patients had no response and there were 96 deaths. Fifty six patients have lost follow-up. Most patients achieved response between 3 and 6 months of therapy. In multivariate analysis the number of neutrophils ≥ 200/uL (p = 0.009), platelets ≥ 12.000/uL (p = 0.018), reticulocyte ≥ 0.5% (p <0.001) and starting treatment after 1997 (p = 0.002) had an impact on overall survival. Patients with 15 or more previous transfusions (p = 0.006) and age ≥ 40 years (p = 0.003) had lower survival. Overall survival was 63% ± 4 and 42% ± 6 for for patients with severe disease and very severe aplastic anemia (p <0.001). The subgroup analysis of patients under 10 years old had similar results. Among patients with response, thirty-four remained dependent of CSA. Cumulative incidence of relapse was 28% ± 4 within a median of 4.4 years. Hypertension, gingival hypertrophy and diabetes mellitus were common, but easily controlled. The rate of clonal evolution among this cohort was 7.81% (16 patients developed Paroxysmal Nocturnal Hemoglobinuria, 9 Myelodysplastic Syndrome and 5 Acute Myeloid Leukemia). Conclusion: This study, with a long follow-up, has demonstrated that the overall survival using CSA and PRED is similar to that reported with ATG therapy. Even patients with partial responses had achieved good quality of life, free from transfusions and infections. Survival was influenced by the neutrophils, platelet counts, reticulocyte, number of transfusions, age at diagnosis, and therapy started after 1997. The incidence of clonal evolution was lower when compared to reported trials with ATG + CSA. Disclosures: Oliveira: Alexion: Speakers Bureau. Funke: Novartis, Bristol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pasquini: Novartis, Bristol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Consistent Benefit of Ruxolitinib Over Placebo in Spleen Volume Reduction and Symptom Improvement Across Subgroups and Overall Survival Advantage: Results From COMFORT-I

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 278-278 ◽  
Author(s):  
Srdan Verstovsek ◽  
Ruben A. Mesa ◽  
Jason Gotlib ◽  
Richard S. Levy ◽  
Vikas Gupta ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Symptom Severity ◽  
Research Funding ◽  
Risk Group ◽  
Spleen Volume ◽  
Advisory Committees ◽  
Disease Subtype ◽  
Baseline Hemoglobin

Abstract Abstract 278 Background: Overactive JAK-STAT signaling as a result of gain-of-function mutations (eg, JAK2V617F) and/or high circulating levels of inflammatory cytokines is considered to play a key role in the pathogenesis of myeloproliferative neoplasms. Ruxolitinib, a selective oral inhibitor of JAK1 and JAK2, demonstrated a significant reduction in spleen volume (SV) and improvements in myelofibrosis (MF)-related symptoms in a double-blind placebo-controlled trial (COMFORT-I). The objective of this analysis was to evaluate the efficacy of ruxolitinib across patient (pt) subgroups in COMFORT-I. Methods: Pts with MF were randomized to start placebo or ruxolitinib at a dose of 15 mg or 20 mg PO BID depending on baseline platelet count (100–200 ×109/L or >200 ×109/L, respectively). The dose was optimized for efficacy and safety during treatment. SV change was measured by MRI; MF symptoms were assessed using a daily diary (modified Myelofibrosis Symptom Assessment Form [MFSAF] v2.0) over 1 wk prior to dosing and throughout the 24 wks of dosing. The percent changes from baseline to wk 24 in SV and MFSAF Total Symptom Score (TSS, a measure of combined scores for abdominal discomfort, pain under ribs on left side, early satiety, itching, night sweats, and bone/muscle pain) were compared for ruxolitinib and placebo pts across the following subgroups: MF disease subtype, age, International Prognosis Scoring System (IPSS) risk group, presence/absence of JAK2V617F mutation, baseline hemoglobin, baseline spleen size (palpable spleen length), and baseline TSS. Survival was estimated by Kaplan-Meier method. Changes in SV and TSS Across Subgroups: 309 pts were randomized: 155 to ruxolitinib and 154 to placebo. Ruxolitinib demonstrated consistent benefit compared with placebo in both SV and TSS across all subgroups evaluated (Table). The impact of symptom severity on response was evaluated by baseline TSS quartiles (maximum score for TSS = 60). Ruxolitinib pts with baseline TSS of <8.5, 8.5-<16.5, 16.5-<25.5 and ≥25.5 had mean percent changes in SV of −28.0, −31.4, −31.7 and −34.8, respectively, vs +8.1 for all placebo pts combined. The mean percent change in TSS for these same subgroups was −40.5, −47.2, −48.1 and −48.2 vs +41.8 for all placebo pts combined. These data indicate that pts with modest to marked symptoms all benefit from ruxolitinib therapy in terms of both SV and TSS. Survival Analysis: 13 ruxolitinib and 24 placebo pts died during the study or during extended follow-up (median follow-up of 52 and 51 wks, respectively), representing a hazard ratio (95% CI) of 0.499 (0.254, 0.98) (p=0.0395). For ruxolitinib- and placebo-treated pts, respectively, the probability of survival (95% CI) >48 wks was 0.98 (0.92, 0.99) and 0.90 (0.81, 0.95) for pts with baseline hemoglobin values ≥10 g/dL and 0.84 (0.72, 0.91) and 0.77 (0.63, 0.86) for pts with baseline hemoglobin <10 g/dL. Conclusions: Pts receiving ruxolitinib had higher response rates than placebo based on reductions in SV and improvements in TSS at wk 24 regardless of baseline subgroup: MF disease subtype, age (≤65 or >65 y), IPSS risk group (intermediate-2 or high-risk), presence or absence of JAK2V617F mutation, hemoglobin level (≥10 g/dL or <10 g/dL), palpable spleen length (≤10 cm or >10 cm), and symptom severity (TSS quartile). In addition, the overall survival analysis suggested a benefit with ruxolitinib therapy over placebo. Disclosures: Verstovsek: Incyte: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding. Gotlib:Incyte: Consultancy, Research Funding. Levy:Incyte: Employment, Equity Ownership. Gupta:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Catalano:Incyte: Honoraria; Novartis: Honoraria. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: 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; Celgene: Research Funding; Genzyme: Research Funding. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Winton:Incyte: Consultancy. Arcasoy:Incyte: Research Funding. Lyons:Alexion: Consultancy, Honoraria; Telik: Research Funding; Incyte: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Vaddi:Incyte: Employment. Erickson-Viitanen:Incyte: Employment. Sun:Incyte: Employment. Sandor:Incyte: Employment. Kantarjian:Incyte: Research Funding; Novartis: Consultancy, Research Funding.

Response to Treatment Among SF3B1 Mutated Myelodysplastic Syndromes (MDS): A Case-Control Study from the MDS Clinical Research Consortium (MDS CRC)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1697-1697 ◽  
Author(s):  
Rami S. Komrokji ◽  
Amy E. DeZern ◽  
Katrina Zell ◽  
Najla H. Al Ali ◽  
Eric Padron ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Lower Risk ◽  
Research Funding ◽  
Somatic Mutations ◽  
Response To Treatment ◽  
Wild Type ◽  
Advisory Committees ◽  
Baseline Characteristics ◽  
Matching Criteria

Abstract Introduction Somatic mutations in SF3B1 ,a gene encoding a core component of RNA splicing machinery, have been identified in patients (pts) with myelodysplastic syndrome (MDS). The SF3B1 mutation (MT) is more commonly detected in pts with ring sideroblasts (RS) morphology and is associated with favorable outcome. The pattern of response among SF3B1 mutated MDS pts to available treatment options, including erythropoiesis stimulating agents (ESA), hypomethylating agents (HMA) and lenalidomide is not known. The distinct underlying disease biology among such pts may alter response to treatment. Methods Pts treated at MDS CRC institutions with MT vs wild-type SF3B1 (WT) controls were matched 1:2. Matching criteria were age at diagnosis, year of diagnosis and International Prognostic Scoring System (IPSS) category at diagnosis. IPSS category was split into two groups (Low or Int-1 vs. Int-2 or High). Matching was performed using the R package by calculating a propensity score, which was then used to determine the two most similar WT SF3B1 patients for each SF3B1-mutated pt, without replacement. Additionally, to be included in the population, pts also had to have been treated with one of the following: ESAs, HMA, or lenalidomide. Response to treatment was evaluated by international Working Group criteria (IWG 2006) and classified as response if hematological improvement or better was achieved (HI+). Survival was calculated from date of treatment until date of death or last known follow-up, unless otherwise noted. Results: We identified 48 Pts with MT and 96 matched controls. Table 1 summarizes baseline characteristics comparing MT vs WT SF3B1 cohorts. SF3B1 MT was detected more often in association with RS, as expected. The majority of pts had lower-risk disease by IPSS and revised IPSS (IPSS-R). Pts with MT had higher platelets than controls. The most common concomitant somatic mutations observed were TET2 (30%), DNMT3A (21%), and ASXL1 (7%). Median follow-up time from diagnosis was 35 months (mo). Median overall survival (OS) from diagnosis was significantly longer for patients with SF3B1 MT (108.5 mo (68.8, NA)) than wild-type controls (28.3 mo (22.3, 36.4); p < 0.001). Patients with an SF3B1 MT had a decreased hazard of death (hazard ratio [HR]: 0.49 (95% confidence limits [95% CL]: 0.29, 0.84); p = 0.009) ESA was the first line therapy for 43 pts (88%) with MT and 55 WT Pts (56%). For ESA treated pts, 14 out 40 MT Pts responded (35%) compared to 9/56 among WT Pts (16%), p 0.032. Among those treated with HMA therapy, 5 out 21 (24%) MT pts responded compared to 11/46 (24%) WT Pts (p 0.99). Finally, for Pts treated with lenalidomide 4/16 (25%) and 4/21 (19%) responded among SF3B1 MT and WT Pts respectively, p 0.7. Conclusions SF3B1 somatic mutation in MDS is commonly associated with RS, lower risk disease, and better OS. Pts with SF3B1 mutation had higher response to ESA compared WT SF3B1. No difference in response to HMA or lenalidomide was observed compared to WT patients. Response rates to lenalidomide and HMA were low in both MT patients and controls. Biologically rational therapies are needed that target this molecular disease subset. Table 1. Baseline characteristics SF3B1 MT (n=48) SF3B1 WT (n=96) P value Age median 65 67 0.6 Gender male 29 (60%) 64(67%) 0.5 Race White 44/45 (98%) 83/90 (92%) 0.34 WHO classification RA RARS RCMD RARS-T Del5 q RAEB-I RAEB-II MDS-U MDS/MPN CMML 3 24 8 4 1 3 3 2 0 0 6 9 17 2 6 10 9 3 11 9 IPSS Low Int-1 Int-2 High 29 (60%) 16 (33%) 3 (6%) 0 21 (22%) 69 (72%) 4 (4%) 2 (2%) < 0.001 IPSS-R Very low Low Intermediate High Very High 15 (31%) 26 (54%) 5 (10%) 2 (4%) 0 11 (11%) 37 (39%) 26 (27%) 18 (19%) 4 (4%) <0.001 Lab values (mean) Hgb Platelets ANC myeloblasts 9.7 274 2.63 1 9.6 108 1.92 2 0.46 <0.001 0.04 0.05 Disclosures Komrokji: Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Incyte: Consultancy; Pharmacylics: Speakers Bureau. Padron:Novartis: Speakers Bureau; Incyte: Research Funding. List:Celgene Corporation: Honoraria, Research Funding. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

Long-Term Responders after Brentuximab Vedotin: Experience on 57 Patients with Relapsed and Refractory Hodgkin and Anaplastic Large Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2725-2725 ◽  
Author(s):  
Pier Luigi Zinzani ◽  
Letizia Gandolfi ◽  
Beatrice Casadei ◽  
Cinzia Pellegrini ◽  
Alessandro Broccoli ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Median Number ◽  
Brentuximab Vedotin ◽  
Advisory Committees ◽  
Large Cell Lymphoma

Abstract Brentuximab vedotin (BV) is an antibody drug-conjugate targeting CD30 linked to monomethyl auristatin E. Several studies have shown the efficacy of BV in patients with refractory or relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). We reviewed our clinical database to evaluate the long-term efficacy of this treatment. From July 2009 to February 2015, 57 patients were treated with BV in our Institute: 43 with a diagnosis of HL and 14 with sALCL. Thirty-six were males and 21 were females, with a median age of 33 years (range 16-77). All of them had been heavily pretreated before BV with a median number of previous therapies of 3 (range 2-10). Thirty-nine had refractory disease and 18 were relapsed. Autologous stem cells transplantation had failed in 30 patients. BV was administered at a dosage of 1.8 mg/mq, every 21 days, for a maximum of 16 cycles. The median number of cycles was 8 (range 2-16); 13 patients completed the entire schedule. The best overall response rate was globally 57,8% (33 of 57 patients), including 25 (43.8%) complete responses (CR): 18 with HL and 7 with sALCL. At present, 20/25 (80%) patients are still in continuous CR (CCR) with a median follow up of 9 months (range 3-41): 10 of them have consolidated the response with a stem cell transplantation (SCT) (4 auto-SCT and 6 allo-SCT) and 10 patients have remained in CR without any other therapy after BV. Among these long-term responders without any consolidation (7 patients with HL and 3 with sALCL), the median follow-up is 12 months (range 3-37); in particular there are 3 patients in CCR after at least 24 months. The global overall survival rate at 68 months is 71% (no patients with sALCL dead) and the median overall survival has not been reached yet. The global progression-free survival rate at 48 months is 30%, the median is achieved at 11,7 months. Toxicity was primarily neurological with peripheral sensory symptoms (30%) and motor neuropathy (5%); the majority was grade 3 in severity (8 patients). This study confirms the safety and the high efficacy of BV that can be considered an effective treatment in patients with relapsed or refractory HL or sALCL. This drug can induce a durable complete response representing a "bridge" to auto-SCT or allo-SCT. However our data show a subset of patients that can be considered "long-term responders", who have remained in CCR without any consolidation after BV. Disclosures Zinzani: Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Cavo:Janssen: Honoraria; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria.

A Simple Score, Based on Geriatric Assessment, Predicts Survival in Elderly Newly Diagnosed Chronic Lymphocytic Leukemia Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2036-2036
Author(s):  
Stefano Molica ◽  
Diana Giannarelli ◽  
Luciano Levato ◽  
Rosanna Mirabelli ◽  
Domenico Levato ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Board Of Directors ◽  
Daily Living ◽  
Lymphocytic Leukemia ◽  
Clinical Staging ◽  
Activity Of Daily Living ◽  
Advisory Committees ◽  
Frailty Score

Abstract BACKGROUND: Clinical outcome of patients with chronic lymphocytic leukemia (CLL) is often poor due to the high prevalence of comorbidities as well as functional impairment that characterize this population. However, a consensus on the definition and measurement of frailty is lacking. The present analysis was designed with the aim to develop a simple and easily applicable frailty score to predict overall survival. PATIENTS: On a retrospective basis, a geriatric assessment (GA) has been performed in 113 CLL patients older than 65 years firstly diagnosed after January 2000 at our institution. GA included the Katz Activity of Daily Living (ADL), the Lawton Instrumental Activity of Daily Living (IADL) and the Cumulative Illness Rating Scale (CIRS). Median age of patients was 71 years (range,65-90) and 32.7% were older than 75 years. According to the Rai staging system 48 (42.4%) patients were in stage 0, 47 (41.6%) in stage I-II and 18 (16%)in stage III-IV. Eighteen patients (16%) had a CIRS score higher than 6, 17 (15%) an ADL score lower than 5 and 21 (18.5%) an IADL score lower than 6. RESULTS: After a median follow-up time of 66 months (range,3-330) 29 (25,6%) out of 113 patients have died and 58 (51.3%) received therapy (i.e., 24 at the diagnosis and 34 after a median follow-up time of 29 months [range, 6-136 months]). Advanced age (HR=3.40), functional decline on ADL (HR=2.90) and IADL (HR=2.70), presence of comorbidities as assessed by CIRS score (HR=2.09), ECOG performance status (HR=4.94) and Rai clinical staging (stage 0 vs I-II, HR=3.65; stage 0 vs III-IV, HR=9.09) were all variables significant in univariate analysis. In a multivariate analysis which did not included Rai clinical staging a higher risk of death was observed for patients older than 75 years (HR=3.11; 95% CI, 1.60-6.06; P=0.001), with ADL lower than 5 (HR 3.50; 95% CI: 1.50-8.40; P=0.02) and CIRS higher than 4 (HR=2.09; 95% CI,1.08-4.05;P=0.03). An additive frailty score based on the integer part of HRs (i.e., 1 point for HR 1.1-1.9; 2 points for HR 2.0-2.9) was then calculated. By combining the risk scores (range, 0-8) for these variables, patients were stratified according to a cutoff finder analysis into 3 distinctive risk groups for overall survival : fit (score = 0, 53,3%), intermediate-fit (score=1-5; 41.5%) and frail (score= 6-8,10%). Median overall survival of patients belonging to fit, intermediate-fit and frail group was as follows: fit, 174 months [95% CI:126-222]; intermediate-fit, 104 months [95% CI:82-127]; frail, 37 months [95% CI:3-71] (P<0.0001)(Fig. 1). The predictive accuracy of our score using Harrell c-index was 0.70 (95% CI:0.53-0.87). Finally, in a head-to-head comparison with Rai clinical staging, by Cox multivariate analysis, our frailty score retained its prognostic significance (fit vs intermediate-fit, HR,3.41 [95% CI,1.63-7.15], P=0.001; fit vs frail, HR, 12.06 [95% CI,3.33-43.67], P<0.0001). CONCLUSIONS: This study represents the first attempt to develop an additive scoring system for CLL based on functional status, comorbidities and age. GA is a sensitive predictor of clinical outcome and could be used for selecting patients to treat with novel therapies. Figure 1 Figure 1. Disclosures Molica: Gilead Sciences: Speakers Bureau; Roche Italy: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Final Overall Survival Results of a Randomized Trial Comparing Bortezomib Plus Pegylated Liposomal Doxorubicin with Bortezomib Alone in Subjects with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3448-3448
Author(s):  
Robert Z. Orlowski ◽  
Arnon Nagler ◽  
Pieter Sonneveld ◽  
Joan Bladé ◽  
Roman Hajek ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Pharmaceutical Research ◽  
Phase Iii ◽  
Advisory Committees ◽  
Grant Support ◽  
Johnson Pharmaceutical Research

Abstract Introduction Previous results of an open-label, randomized, controlled, multicenter phase III study (DOXIL-MMY-3001) demonstrated that bortezomib+pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in treating subjects with relapsed or refractory multiple myeloma (MM) whose disease had failed one or more lines of prior therapy. The risk of developing disease progression was significantly reduced by 45% with bortezomib+PLD (median time to progression (TTP) with bortezomib+PLD: 9.3 months, bortezomib: 6.5 months; HR=1.82, 95% confidence interval (CI) [1.41, 2.35]; p=0.000004). In the interim analysis, the 15-month overall survival (OS) rate for bortezomib+PLD was 76% (95% CI [70%, 83%]) compared with 65% (95% CI [58%, 73%]) for bortezomib alone (p=0.03)(Orlowski et al JCO 25: 3892-3901, 2007). A protocol-defined analysis of the final survival data of this study is provided here. Methods Subjects with confirmed MM, ECOG status 0 to 1, platelets ≥75,000/mm3, hemoglobin ≥8.0 g/dL, absolute neutrophils ≥1,000/mm3, and creatinine clearance ≥30 mL/min were randomized to bortezomib (bortezomib 1.3 mg/m2, intravenous, days 1, 4, 8, and 11 of an every 21-day cycle), or bortezomib+PLD (same bortezomib+PLD 30 mg/m2 intravenous on day 4). Randomization was stratified according to serum β2-microglobulin levels (≤2.5, >2.5 and ≤5.5, or >5.5 mg/L) and response to prior treatment (response followed by progression, or primary refractory). The primary endpoint was TTP; secondary efficacy endpoints included overall survival, progression-free survival (PFS) and overall response rate (complete response [CR] + partial response [PR]). Results A total of 646 subjects (bortezomib+PLD: 324; bortezomib: 322) were randomized between December 2004 and March 2006. In the pre-planned interim analysis, the study met its primary and other secondary end points. The study continued for long-term survival follow-up. At the clinical cutoff of 16 May, 2014, for the final survival analysis with a median follow-up of 103 months, 79% of subjects were dead (bortezomib+PLD: 253 [78%]; bortezomib: 257 [80%]), 6% withdrew consent, 4% were lost to follow-up, and 11% were still alive. Median OS in bortezomib+PLD–treated subjects was 33.0 months (95% CI [28.9, 37.1]) versus 30.8 months (95% CI [25.2, 36.5]) in bortezomib-treated subjects (HR=1.05, 95% CI [0.88, 1.25]; p=0.6068). The types of salvage therapies utilized included dexamethasone (49.1%), thalidomide (31.0%), cyclophosphamide (28.5%), melphalan (22.9%), lenalidomide (21.8%), bortezomib (20.4%) and doxorubicin (8.0%), which were well-balanced between the two treatment groups. Conclusion Despite inducing a superior TTP, long-term follow-up revealed that PLD+bortezomib-treatment did not improve the OS compared with bortezomib alone in subjects with relapsed or refractory MM. The inability to confirm the early survival advantage may be due to the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase III trials. Disclosures Orlowski: Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sonneveld:Orthobiotech;: Consultancy. Bladé:Celgene: Grant support, Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Spencer:Hospira: Research Funding. Robak:MorphoSys AG: Research Funding. Dmoszynska:Johnson & Johnson Pharmaceutical Research & Development: Research Funding. Horvath:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Research Funding. Sutherland:OrthoBiotech: Consultancy. Xiu:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Employment, Equity Ownership. Parekh:Johnson & Johnson Pharmaceutical Research & Development: Employment, Equity Ownership. Miguel:Janssen Cilag: Consultancy, Honoraria.

scholarly journals Phase 2 Study of Nilotinib 400 Mg Twice Daily in Newly Diagnosed Patients with Accelerated Phase of Chronic Myeloid Leukemia, Results after 5.7 Years of Follow-up

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3011-3011 ◽  
Author(s):  
Lucia Masarova ◽  
Jorge E. Cortes ◽  
Keyur P. Patel ◽  
Susan M. O'Brien ◽  
Graciela M. Nogueras González ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 2 ◽  
Advisory Committees ◽  
Free Survival ◽  
Genetics Research ◽  
Phase 2 Study ◽  
Grade 3

Abstract OBJECTIVES Nilotinib is a potent, second generation inhibitor of BCR-ABL tyrosine kinase (TKI) and represent a standard of care for patients with chronic myeloid leukemia (CML), including accelerated phase (AP-CML). In 2005, we initiated a phase 2 study of nilotinib 400 mg twice daily as a frontline therapy in patients with AP-CML, and herein present the efficacy and safety data after a median follow-up of 68.4 months (range, 0.3-124.8). METHODS This was a prospective, single institution, phase 2 study in patients of age ≥18 years with a newly diagnosed, untreated AP-CML (except for <1 month of previous imatinib) defined according to MD Anderson criteria (Kantarjian, 1988). Patients were treated with nilotinib 400 mg twice daily (BID). Data are presented on an intention to treat analysis with a cutoff date of June 30st, 2018. Response criteria are standard. Fisher exact test and χ2 were used for analysis of categorical variables; and survival probabilities were estimated using the Kaplan-Meier method. Time to events (e.g., overall survival, event free survival) was calculated from the date of treatment to the date of an event or to last follow-up as previously reported (Cortes et al, 2010). RESULTS Twenty two patients of a median age of 53.7 years (range, 26-79.7) were enrolled. Table 1 summarizes clinical characteristics of all patients. The median treatment duration was 47.3 months (range; 0.3-124.4), and the median follow-up 68.4 months (range, 0.3-124.8). All patients discontinued study as of January 2017 due to planned study closure; but 11 patients (50%) continued on nilotinib off protocol at data cut-off (400 mg BID [3]; 300 mg BID [2]; and 200 mg BID [6]). Median time to treatment discontinuation in the remaining 11 patients was 12.9 months (range, 0.3-112); reason for discontinuation was: inadequate response [3], toxicity [2], non-compliance/financial [4]; elective discontinuation after sustained MR4.5 >2 years [1]; and death due to stroke [1]. Sixteen patients (73%) achieved complete hematologic response (CHR). Overall rates of CCyR, MMR, MR4.5 and CMR (undetectable transcripts with at least 100,000 ABL copies) were 73%, 73%, 55%, and 41%, respectively. Median times to CCyR, MMR, and MR4.5 were 2.9 months (range, 2.7-6.4), 5.7 months (range, 2.7-99.2) and 6.0 months (range, 2.7-36), respectively. Seven patients (32%) achieved sustained MR4.5 >2 years. In total, 4 patients lost their best achieved response (CHR [1], CCyR [2] and MR4.5 [1]) while on study. All events were associated with acquired ABL domain mutation; Y253H [2], T315I [1], and F359I [1] with a median time to detection of 16.7 months (range, 7-40). During the study conduct, one patient progressed to blast phase after 2 months on nilotinib. Two patients died while on study, one due to stroke and one due to unrelated medical condition, after being on therapy for 3 and 0.4 months, respectively. One patient electively discontinued nilotinib after being in sustained MR4.5 for 107 months, and remains in MR4.5 after 6 months off therapy. Estimated overall survival and event free survival at 5 years were 84% and 70%, respectively (Figures 1a & 1b). On univariate analysis, age >55 years was associated with lower rate of MMR (p = 0.034; HR 0.34; 95% CI 0.12-0.92); MR4 (p = 0.013; HR 0.25; 95% CI 0.08-0.75); and MR4.5 (p = 0.01; HR 0.15; 95% CI 0.04-0.63). Overall survival was inferior in patients older than 55 years (p = 0.014; HR 2.4; 95% CI 2.36-not estimated); and in those with > 1 AP-CML defining abnormality (p = 0.018; HR 9.53; 95% CI 0.98-92). The most frequent non-hematologic adverse events (AEs) were hyperbilirubinemia (63% of patients), rash (63%), hypertension (59%), and transaminitis (50%). Grade ≥3 AEs observed in more than one patient were hyperbilirubinemia (n=2), and transaminitis (=2). Two patients developed arterio-thrombotic AEs: stroke and myocardial infarction (one each). Hematologic AEs included (all grades; grade ≥3): anemia (36%; 9%), thrombocytopenia (32%; 14%) and neutropenia (14%; 9%). Two patients (9%) discontinued therapy due to nilotinib related AE, one for G3 peripheral neuropathy and one for G3 hyperbilirubinemia with G2 thrombocytopenia. CONCLUSION Nilotinib is safe and highly effective in patients with AP-CML, and induces fast and durable responses. More than 50% of patients can achieve MR4.5. Clinical trial.gov: NCT00129740. Disclosures Cortes: novartis: Research Funding. O'Brien:Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Kite Pharma: Research Funding; Regeneron: Research Funding; Vaniam Group LLC: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Alexion: Consultancy; Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; TG Therapeutics: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding; Immunogen: Research Funding; abbvie: Research Funding; cellectis: Research Funding. Verstovsek:Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kadia:Celgene: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding.

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