CML Patients In Clinical Trials Represent Fairly Well The General Population Of CML Patients: A Comparative Analysis Of 5803 Patients From The EUTOS Registry

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2735-2735 ◽  
Author(s):  
Verena S Hoffmann ◽  
Doris Lindoerfer ◽  
Markus Pfirrmann ◽  
Susanne Saussele ◽  
Andreas Hochhaus ◽  
...  
Keyword(s):  
General Population ◽  
Board Of Directors ◽  
Risk Score ◽  
Peripheral Blood ◽  
Research Funding ◽  
Chronic Phase ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Study Section ◽  
Oncology Research

Abstract Introduction The centerpiece of the European Treatment and Outcome Study (EUTOS) for Chronic Myeloid Leukemia (CML) is a registry collecting representative samples of CML patients in Europe. The In-Study section of the registry combines data of patients enrolled in investigator-sponsored prospective studies of treatment with imatinib-based regimens. The population-based (PB) section includes data of all newly diagnosed CML patients in specified regions of 27 European countries in an attempt to represent the general population of CML patients. Aims There is a common assumption that patients enrolled in prospective trials are highly selected, do not represent the ‘typical’ patient and that thus the results of such trials may not be easily generalized to all patients. Thus we analyzed possible differences in the baseline characteristics of the two patient groups. Available were age, sex, EUTOS score, phase of disease, spleen enlargement, platelets, leukocytes, and percentages of blasts, eosinophils, and basophils in peripheral blood. Methods For all analyzed factors we calculated distribution parameters or percentages depending on the scale of the factor. To identify significant differences we used χ2-tests and Mann-Whitney U-tests. Level of significance was 0.05. Results The In-Study section included 2346 patients from study groups in Germany, Italy, France, Spain, the Nordic study group, the Netherlands, and the United Kingdom, newly diagnosed from 2002 to 2006. The PB section of the registry included 3457 patients newly diagnosed with CML from 2008 to 2012 in 27 European countries. The median age at diagnosis of In-Study patients (51 years (18-88)) was significantly lower than the age of the general population newly diagnosed with CML (56 years (18-99), p<0.0001). Also, while in the PB section the percentage of male patients was 54%, in the In-Study section the percentage was significantly higher (60%, p<0.0001). The median spleen size enlargement (cm below costal margin) did not differ significantly between the two groups (In-Study (1 cm (0-38), PB section 0 cm (0-40)). While 7% of patients in the PB section were not in chronic phase, this was only true for less than 1% of patients included into the In-Study section. Accordingly, there were significant differences (both p<0.0001) regarding percentages of blast cells in peripheral blood (In-Study: 1% (0-14), PB 1% (0-92)) and leukocytes (In-Study: 74 x109/L (20-650), PB 85 x109/L (3-932)). There were no differences in percentage of basophils, eosinophils and in platelet count. The EUTOS risk score was developed to predict the treatment success of patients in chronic phase and thus is calculated for patients in chronic phase only. In the In-Study section 10.5% of patients had a high EUTOS risk score while the percentage in the general population was 11.4%. The resulting difference was not significant (p=0.3374). Conclusions With a total of 5803 patients included in the two sections of the EUTOS registry analyzed for this work, the combined data allow a unique insight into the characteristics of CML patients in Europe. The comparison between the In-Study and the PB sections shows some important differences between the two populations, such as age and sex distribution. However, several other clinical and hematological factors which are known to be predictive for treatment outcome did not differ substantially. We conclude that patients enrolled in investigator-sponsored studies represent fairly well the general population of CML patients in Europe, with the exception of sex and age distribution, which may limit the value of the calculations of overall survival because those are affected by both age and gender. Disclosures: Hoffmann: Novartis Oncology: Research Funding. Lindoerfer:Novartis Oncology: Research Funding. Pfirrmann:Novartis: Consultancy. Saussele:Novartis Oncology: Honoraria, Research Funding. Hochhaus:Novartis: Research Funding; Bristol Myers Squibb: Research Funding. Rosti:Novartis: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau. Mayer:Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding. Castagnetti:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Turkina:Bristol Myers Suibb: Consultancy; Novartis Pharma: Consultancy. Zaritskey:University of Heidelberg: Research Funding. Steegmann:Novartis Pharma: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Cervantes:Bristol Myers Squibb: Speakers Bureau; Teva Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Novartis: Speakers Bureau. Porkka:BMS: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Griskevicius:Novartis: Consultancy, Research Funding. Panagiotidis:GSK: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Hehlmann:Novartis: Research Funding; Bristol Myers Squibb: Consultancy. Baccarani:Novartis: Research Funding.

scholarly journals VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1835-1835 ◽  
Author(s):  
Katrina M Piedra ◽  
Hani Hassoun ◽  
Larry W. Buie ◽  
Sean M. Devlin ◽  
Jessica Flynn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cancer Trial ◽  
Oncology Research ◽  
Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: 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, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

Timing of Daratumumab Administered Pre-Mobilization in Multiple Myeloma Impacts Pre-Harvest Peripheral Blood CD34+ Cell Counts and Plerixafor Use

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-16
Author(s):  
Danny Luan ◽  
Paul J Christos ◽  
Michael Ancharski ◽  
Danielle Guarneri ◽  
Roger Pearse ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Stem Cell Mobilization ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Peripheral Blood Cd34 ◽  
Hematopoietic Recovery ◽  
Cell Mobilization

Background: Daratumumab (DARA) is a monoclonal antibody which targets CD38 on plasma cells and B cell progenitors. DARA has been effectively combined with other therapies in newly diagnosed and relapsed/refractory multiple myeloma (RRMM), while DARA-based induction regimens in transplant-eligible patients (pts) are increasingly being used in clinical practice. Given that hematopoietic stem cells also express CD38, DARA may potentially affect stem cell mobilization and hematopoietic reconstitution following autologous stem cell transplant (ASCT). Although no clinically significant impact of DARA on stem cell mobilization or hematopoietic recovery was described in large phase 3 trials of triplet induction regimens +/- DARA in newly diagnosed MM, stem cell yields were lower and plerixafor more commonly used in the DARA-containing arms [Moreau et al, Lancet 2019; Voorhees et al, Blood 2020]. Significantly longer time to neutrophil (PMN) engraftment was also reported in pts receiving DARA-based induction who underwent upfront ASCT [Al Saleh et al, Am J Hematol 2020]. In this study, we examine the impact of timing of DARA administration pre-mobilization on day 4 pre-harvest peripheral blood CD34 cell count, stem cell apheresis yield, and post-ASCT engraftment. Methods: Between 1/1/2016 and 12/31/2019, newly diagnosed and RRMM pts receiving DARA-based induction regimens with ≥1 dose of DARA administered within 1 month prior to stem cell mobilization were identified retrospectively and compared to matched controls receiving similar induction regimens without DARA. Granulocyte colony-stimulating factor (G-CSF) was administered per institutional standards and plerixafor added based on day 4 pre-harvest peripheral blood CD34 counts. PMN and platelet engraftment post-ASCT was defined as the first of 3 consecutive days with sustained PMN count &gt;500 x 106/L and independence from platelet transfusion in the preceding 7 days with a count &gt;20 x 109/L, respectively. Pre-harvest peripheral blood CD34 counts and stem cell apheresis yields were obtained from the Cellular Therapy Laboratory at NewYork-Presbyterian Hospital. The study was approved by the Weill Cornell Medicine IRB. Results: We identified 16 pts who received DARA-based induction with ≥1 dose of DARA administered within 1 month of apheresis (DARA group) and 16 non-DARA-containing regimen-matched controls (non-DARA group). Demographics of the DARA and non-DARA groups were well matched (Table 1). DARA pts received their last dose of DARA a mean of 17.3 days prior to the first day of apheresis, with 8 pts receiving their last dose within 2 weeks and the remaining 8 pts between 2 weeks and 1 month prior. Overall, mobilization outcomes were inferior in the DARA group (Table 2). DARA pts had significantly lower day 4 pre-harvest peripheral blood CD34 counts compared to non-DARA pts (17.2 vs 35.4 cells/µL; P=0.0146). Institutional algorithm required plerixafor to be given for day 4 CD34 count ≤40 cells/µL. Fifteen of the 16 DARA pts received plerixafor vs. 11 non-DARA pts (P=0.07). Additionally, DARA pts required significantly more apheresis days (2.4 vs 1.6 days; P=0.0279). Differences in stem cell yield were not significant (8 vs 10 x106cells/kg; P=0.1391). Hematopoietic recovery post-ASCT was not affected by DARA administered in the month preceding mobilization. Conclusions: In summary, we report lower day 4 pre-harvest peripheral blood CD34 count, increased requirement for plerixafor, and longer apheresis duration in newly diagnosed and RRMM pts receiving DARA within 1 month ofstem cell mobilization. These limitations are largely overcome by plerixafor usage which, combined with G-CSF, resulted in successful stem cell collection in all patients. Limitations in our study include small sample sizes, retrospective control selection, and fewer pts in the DARA group achieving ≥VGPR prior to mobilization. Nevertheless, our findings are consistent with inferior mobilization outcomes reported in the DARA-containing arms of phase 3 trials of triplet induction +/- DARA and highlight the nearly universal requirement for plerixafor usage when DARA is administered within a month prior to apheresis. Prospective study of day 4 pre-harvest peripheral blood CD34 counts and other predictors of stem cell yield should be incorporated into future clinical trials of CD38 monoclonal antibody-based induction regimens for transplant-eligible MM pts. Disclosures Rossi: Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Niesvizky:GSK: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Rosenbaum:Amgen: Research Funding; GlaxoSmithKline: Research Funding; Akcea: Honoraria; Celgene: Honoraria; Janssen: Research Funding.

scholarly journals Clonal Hematopoiesis Prevalence Increases throughout Treatment of Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1091-1091
Author(s):  
Tarek H. Mouhieddine ◽  
Chidimma Nzerem ◽  
Robert A. Redd ◽  
Andrew Dunford ◽  
Matthew Joseph Leventhal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Hematologic Malignancy ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Clonal Hematopoiesis ◽  
First Time ◽  
Time Point

Abstract Background: Recent studies have identified clinical and genomic factors contributing to worse clinical outcomes in patients with multiple myeloma (MM). Clonal hematopoiesis (CH) reflects the presence of somatic driver mutations in the blood or marrow of otherwise asymptomatic individuals. Using a variant allele frequency (VAF) cutoff of 2%, we recently reported CH in 21.6% of MM patients at the time of autologous stem cell transplant (ASCT) and found it was associated with shorter overall survival (OS) and progression-free survival (PFS) in those who did not receive maintenance therapy with an immunomodulatory drug (IMiD). However, this finding was based on a single tertiary center and only included MM patients who received ASCT. Methods: We studied a larger cohort of 986 newly diagnosed MM cases. Whole-exome sequencing (WES) data of peripheral blood and bone marrow samples of 986 MM patients (523 transplanted and 463 non-transplanted) from the Multiple Myeloma Research Foundation (MMRF) Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass, NCT0145429) study were analyzed. Both peripheral blood and tumor samples were analyzed to filter out myeloma mutations that could be contaminating the peripheral blood. Given the lower depth of coverage compared to prior targeted sequencing studies, small clones with a VAF below 2% were not detected. Altogether, the WES samples had a total depth of coverage of 117.68X. All data were analyzed using R version 3.5.0 (R Core Team). Results: Among the total cohort, 113 CH mutations were detected in 101/986 (10.24%) patients. CH was detected in 42/523 (8.03%) transplanted patients, compared to 59/463 (12.74%) non-transplanted patients. The most commonly mutated genes were DNMT3A, TET2, ASXL1, PPM1D, and TP53. The median age of the cohort was 63 years (range: 27 - 93), 60% were male, and median follow-up was 3.9 years (95% CI: 3.7 - 4.0). The presence of CH was associated with age (69 vs. 62 years, P &lt; 0.001). As expected, the median age of transplanted patients was lower (60 vs. 67 years) than in the non-transplanted group, which likely explains the higher prevalence of CH detected in the non-transplanted group. CH was associated with recurrent bacterial infections (P = 0.01) and increased cardiovascular disease (P = 0.006), but not with cerebrovascular disease (P = 0.74) or coagulopathies (P = 0.65). There was a trend towards worse PFS in non-ASCT patients with CH who were not treated with IMiDs (1.8 years) compared to non-CH IMiD-treated patients (2.7 years) (P &lt; 0.001). A CH effect on PFS was not detected in ASCT patients. OS was not different in those with or without CH in both ASCT and non-ASCT groups. 8 (0.8%) patients developed a second hematologic malignancy. CH at the time of MM diagnosis was not associated with an increased risk of developing a second hematologic malignancy (P = 0.58). To determine whether CH clones emerged or evolved during treatment, we examined serial samples from 52 patients (36 ASCT patients and 16 non-transplanted patients) with sequential samples. The median time between the first and second time point was 3.1 years (range: 1.0 - 5.4 years). At the first time point, only 3/52 (5.8%) patients had CH, but that number increased to 13/52 (25.0%) at the second time point. Five out of the 13 (38%) were non-transplanted patients. All but 1 patient were exposed to IMiDs. The most common emerging mutated gene was DNMT3A, found in 7 patient samples at the second time point, compared to 2 patients at the first time point. Conclusion: Using WES in a large cohort of newly diagnosed MM patients, we detected CH in 10.2% (VAF ≥ 2%) of patients. CH and non-IMiD treatment confers a shorter PFS in non-transplanted MM patients. However, throughout IMiD-based treatment, MM patients tend to acquire and/or expand previously undetected CH clones, particularly DNMT3A. The clinical significance of this clonal expansion during therapy is yet to be elucidated, and for now, this observation does not yet change clinical management. Figure 1 Figure 1. Disclosures Steensma: Novartis: Current Employment. Ebert: Deerfield: Research Funding; GRAIL: Consultancy; Exo Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Skyhawk Therapeutics: Membership on an entity's Board of Directors or advisory committees. Soiffer: NMPD - Be the Match, USA: Membership on an entity's Board of Directors or advisory committees; Gilead, USA: Other: Career Development Award Committee; Rheos Therapeutics, USA: Consultancy; Kiadis, Netherlands: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics, USA: Other: Data Safety Monitoring Board; Precision Biosciences, USA: Consultancy; Jazz Pharmaceuticals, USA: Consultancy; Jasper: Consultancy; Takeda: Consultancy. Sperling: Adaptive: Consultancy. Getz: Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; IBM, Pharmacyclics: Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

scholarly journals A Multicenter, Open-Label Feasibility Study of Daratumumab with Dose-Adjusted EPOCH in Newly Diagnosed Plasmablastic Lymphoma: AIDS Malignancy Consortium 105

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1595-1595 ◽  
Author(s):  
Carlyn Rose Tan ◽  
Stefan K. Barta ◽  
Shelly Y. Lensing ◽  
Ariela Noy
Keyword(s):  
Clinical Trial ◽  
B Cell ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hiv Positive ◽  
Newly Diagnosed ◽  
Advisory Committees

Background: Plasmablastic lymphoma (PBL) is an aggressive large B-cell lymphoma commonly associated with HIV, immunosuppression, old age, and autoimmune disorders, but can be seen in immunocompetent patients. Intensive regimens, including EPOCH, have only a median overall survival between 9 to 15 months. Complete response rates are 40% to 65%. Patients with refractory or relapsed disease typically have a dismal prognosis. Little progress has been made in treating PBL without a single dedicated clinical trial to date. PBL has morphologic and immunophenotypic characteristics overlapping high-grade B-cell lymphoma and multiple myeloma. It is CD20 negative and positive for plasma cell markers, including CD38, CD138, and MUM-1/IRF-4, with a proliferation index typically > 90%. Daratumumab (DARA) is a human IgG1k anti-CD38 monoclonal antibody (mAb). CD38 is a transmembrane receptor with enzymatic activity highly expressed on the surface of plasma cells and plasmablasts. DARA induces directed cell killing of CD38 expressing cells including complement dependent cytotoxicity and antibody-dependent cell cytotoxicity (ADCC). DARA has significant activity as a single agent and part of combination therapy in myeloma. In non-Hodgkin lymphoma (NHL), DARA resulted in synergistic reduction of tumor growth when combined with rituximab and CHOP (R-CHOP) in follicular lymphoma systemic xenograft models and induced dose-dependent ADCC on mantle cell and follicular lymphoma cells lines in the presence of peripheral blood mononuclear cells in vitro (Pérez-Galán P, et al. Hematol Oncol. 2017). In addition, in vivo models using DLBCL (SU-DHL-6) cells injected in SCID mice showed superiority of DARA in combination with CHOP vs DARA alone (63% vs 55%, p <0.01). In a patient-derived DLBCL model with high CD38 expression, DARA with CHOP or R-CHOP showed tumor regression, and tumors did not regrow when treatment with DARA was stopped after 3 doses. (Doshi P, et al. Haematologica. 2014). We designed an innovative approach to treat PBL using a combination of chemotherapy and directed immunotherapy with a mAb. We hypothesize that adding the potent CD38-directed mAb DARA to DA-EPOCH is safe and feasible and results in improved outcomes in PBL similar to the benefit seen with adding rituximab to a CHOP or EPOCH backbone in other DLBCL subtypes. This will be the first clinical trial dedicated to patients with PBL. Study Design and Methods: This is a non-randomized, multicenter study conducted by the AIDS Malignancy Consortium. Both HIV negative and HIV positive PBL patients ≥ 18 years old with Stage II to IV PBL or Stage I with elevated LDH and/or bulky tumor, who have measurable disease and adequate organ function are eligible. HIV positive patients must have CD4 ≥ 100 cells/μL and be on concurrent combination antiretroviral therapy (cART) or agree to start cART. Key exclusion criteria include receiving ≥ 1 prior cycle of combination chemotherapy, hepatitis B seropositivity, and active CNS involvement. DARA will be given in conjunction with DA-EPOCH every 21 days for 6 cycles. DARA 16 mg/kg will be administered intravenously weekly for the first 3 cycles on days 1, 8, and 15, then on day 1 for cycles 4-6. The primary aim is to determine the percentage of newly diagnosed PBL patients who complete ≥ 3 cycles of DARA with DA-EPOCH irrespective of HIV status. We expect that 85% of patients will complete ≥ 5 cycles of DA-EPOCH alone based on the CALGB 50303 study (Bartlett NL, et al. JCO. 2019). Allowing for a lower proportion completing with the addition of DARA, we hypothesize that > 75% of patients will complete ≥ 3 cycles of protocol treatment. An early stopping rule for completing <3 cycles will be employed. The planned enrollment is 15 patients. Correlations with clinical outcomes will include immunohistochemistry on tumor specimens and peripheral blood to study EBV clearance and identify predictive biomarkers. We will study non-invasive monitoring by circulating tumor DNA using plasma DNA mutation panels and clonal immunoglobulin. Disclosures Tan: Merck: Research Funding; Bayer: Research Funding; Takeda: Research Funding; Janssen: Research Funding. Barta:Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Seattle Genetics: Honoraria, Research Funding; Celgene: Research Funding; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Mundipharma: Honoraria; Bayer: Consultancy, Research Funding. Noy:NIH: Research Funding; Pharamcyclics: Research Funding; Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; Raphael Pharma: Research Funding. OffLabel Disclosure: Daratumumab is being used off-label on this clinical trial.

First Results of Russian Multicenter Population Base Study of the Incidence of Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4431-4431
Author(s):  
Sergey M. Kulikov ◽  
Olga Yu. Vinogradova ◽  
Ekaterina Yu. Chelysheva ◽  
Marya V. Galayko ◽  
Irina A. Titshenko ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Clinical Symptoms ◽  
Molecular Genetic ◽  
Age Groups ◽  
Chronic Phase ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
First Results ◽  
Collection Data

Abstract Abstract 4431 The European Treatment Outcome Study (EUTOS) is register based international investigation started in June 2007. [1] The aim is to study the epidemiology of CML and to gain insight into the ‘real world’ treatment of patients with CML. Population base section (EUTOS-PBS) is the prospective study directed mostly to epidemiology aims. Russian part of the EUTOS-PBS registry collect data of newly diagnosed patients lived in 7 large regions of about 10 millions of population totally. EUTOS-PBS inclusion criteria are following: newly diagnosed CML (Ph +/BCR-ABL) started form 1st October 2009, age: older than 18. Russian CML group includes additional protocol for collection data for patients with clinical symptoms of CML. These patients are included into the roster table and after laboratory confirmation are enrolled into the main phase of the study. Thus, 174 patients were included in pre-phase, 142 (82%) had the diagnosis of CML which was confirmed by cytogenetic/molecular-genetic tests (Ph +/BCR-ABL +), 32 (18%) was not confirmed as CML. Among them 87% (n = 20) - have other Ph–negative chronic myeloproliferative diseases, and also acute leukemia (n = 1), cancer (n = 1), chronic inflammatory processes (n = 1). 142 patients with CML are 73 men, 69 women have the age from 18 to 82 (Me 49) years. 136 (96%) of patients are in the chronic phase, 6 (4%) -in the phase of acceleration, nobody in a blast ñrisis. The standard frequency analysis with adjustment to the standard population of WHO was carried out to estimate distribution. The results was presented in the table 1. As shown registered morbidity in 6 regions is not varied so much: source incidence is 0,58 (0,44–0,69); standardized on WHO incidence is: 0,7 (0,57 – 0,85); per 100 thousands per year. Estimated registered morbidity of CML in Russian regions are in 1.5–2 times less, than published morbidity in western countries. The analysis of the incidence in age stratums (table 2) shows that there is no much growth of age morbidity as expected. It obviously points to low detectability of new CML incidents in senior age categories (are more senior 60 years). This fact is probably the main reason of low total registered morbidity. Tabl.1. Incidence rate of new CML cases in 6 regions of Russia Region population (mln.) N CML for 100000. in year Standard of WHO Mordovia Republic 0.87 14 0.69 0.85 Kirov region 1.46 18 0.53 0.6 Perm territory 2.77 45 0.68 0.8 Bryansk region 1.35 17 0.53 0.65 Irkutsk region 2.55 36 0.56 0.68 Zabaikal's territory 1.36 12 0.44 0.57 Total 10.13 142 0.58 0.7 Table 2.CML incidence in age groups Age groups Male Female Maleandfemale 18–29 0.65 0.57 0.61 30–39 0.86 0.39 0.62 40–49 0.50 0.57 0.54 Conclusion: The CML incidence in Russia regions is underestimated. The main reason is an insufficient CML diagnostic screening in the senior age groups of population. References. 1. http://www.eutos.org/content/registry/documents/documents/e940/infoboxContent941/CML-Registry_February09.pdf Disclosures: Vinogradova: BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Chelysheva:Novartis Pharma: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; MSD: Speakers Bureau. Senderova:Novartis: Consultancy. Turkina:Novartis Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals The Predictive Value of Intracellular Imatinib Levels in Chronic Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4250-4250 ◽  
Author(s):  
Nicholas L Jackson Chornenki ◽  
Christopher M. Hillis ◽  
Isabelle Bence-Bruckler ◽  
Lambert Busque ◽  
Caroline Hamm ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Plasma Levels ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Transcript Levels ◽  
Disease Response ◽  
Log Reduction

Abstract Background: Plasma levels of imatinib have been shown to be predictive of disease response in chronic phase chronic myeloid leukemia (CML). However, the ultimate site of action of imatinib is intracellular. While intracellular imatinib has been reported to be correlated with plasma imatinib, the use of intracellular imatinib for the prediction of clinical outcomes is unclear. The concentration of intracellular imatinib depends on many factors including the level of alpha-1-acid glycoprotein, which binds to imatinib and prevents intracellular uptake, and the OCT-1 transporter, which mediates the influx of imatinib across the plasma membrane of leukemic cells. We conducted the present study of newly diagnosed CML patients with the primary objective of determining if intracellular levels of imatinib two weeks after treatment initiation predicted major molecular response. The secondary objectives were to elucidate the relationships between the levels of OCT-1 and plasma imatinib with intracellular imatinib. Methods: We prospectively studied newly diagnosed chronic phase CML patients in Canada who were treated with standard dose imatinib (400 mg). We measured both intracellular and extracellular (plasma) levels of imatinib by tandem mass spectrometry at two weeks, four weeks, and twelve months after enrollment. Additionally, we measured transcript levels of OCT-1 and BCR-Abl by q-rt-PCR before treatment, at six months, and at twelve months to determine therapeutic response. Results: Eighty-one patients were screened. A total of 76 patients entered the study, and 55 completed the study per protocol. Patient information is shown in Table 1. There was a significant correlation between intracellular imatinib levels at two weeks and a 2-log reduction of BCR-Abl transcript at six months (r=0.390; 95% CI = 0.136 - 0.595; p = 0.004) (Figure 1), but not at twelve months (r=0.183; 95% CI = -0.094 - 0.434; p = 0.194). Notably, intracellular imatinib levels and plasma levels of imatinib were highly correlated at two weeks (r=0.698; 95% CI = 0.559-0.799; p <0.001) and four weeks (0.699; 95% CI = 0.555 - 0.802; p < 0.001) but not between four weeks and twelve months (r= 0.230; 95% CI = -0.040 - 0.469; p = 0.094). There was no correlation between intracellular imatinib levels at two weeks and the pre-treatment OCT-1 transcript level (r=0.072; 95% CI = -0.166 to 0.301; p =0.556). Conclusions: Intracellular imatinib levels at two weeks was moderately predictive of a disease response at six months as indicated by a 2-log reduction in BCR-Abl transcript. OCT-1 transcript levels did not have utility for predicting intracellular imatinib levels. Measurement of intracellular Imatinib levels may prove to have utility in identifying patients who would benefit from adjustments to therapy. Disclosures Hillis: Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Busque:Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy; BMS: Consultancy. Lipton:Bristol-Myers Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Savoie:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Nilotinib Shows Safety and Efficacy in Older Patients (≥ 65 years) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase Comparable with That in Younger Patients with Chronic Myeloid Leukemia in Chronic Phase: Results From ENESTnd,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3768-3768 ◽  
Author(s):  
Richard A. Larson ◽  
Udomsak Bunworasate ◽  
Anna G. Turkina ◽  
Stuart L. Goldberg ◽  
Pedro Dorlhiac-Llacer ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 3768 Background: Data from the phase 3, randomized multicenter ENESTnd trial have demonstrated the superiority of nilotinib over imatinib after 24 months (mo) of follow-up, with significantly higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR), and significantly lower rates of progression to accelerated phase/blast crisis (AP/BC). The current subanalysis evaluated the efficacy and safety of nilotinib 300 mg twice daily (Nil300) and nilotinib 400 mg twice daily (Nil400) in older (≥ 65 years [yrs] at study entry) patients (pts) with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) with a minimum follow-up of 24 mo. Methods: In ENESTnd, 846 pts stratified by Sokal risk score were randomized 1:1:1 to Nil300 (n = 282), Nil400 (n = 281), or imatinib 400 mg once daily (n = 283). Pts with impaired cardiac function or ECOG performance status > 2 were excluded. Rates of CCyR and MMR by 24 mo, progression to AP/BC on treatment, and safety were evaluated according to age group (< 65 vs ≥ 65 yrs) in the 2 nilotinib arms. Safety data are reported for any pt who received ≥ 1 dose of nilotinib (n = 279, Nil300; n = 277, Nil400). Results: 36 pts (13%) and 28 pts (10%) were ≥ 65 yrs old in the Nil300 and Nil400 arms, respectively. Of the pts aged ≥ 65 yrs, 51/64 (80%) had an ECOG performance status of 0 at baseline and 60/64 (94%) had intermediate or high Sokal risk scores. Of the older pts, 8 (22%) on Nil300 and 6 (21%) on Nil400 had type 2 diabetes at baseline. CCyR rates by 24 mo were 83% and 68% among older pts treated with Nil300 and Nil400, respectively, and 87% for pts aged < 65 yrs in each nilotinib arm. By 24 mo, MMR was achieved by 72% and 61% of older pts on Nil300 and Nil400, respectively; in pts aged < 65 yrs, the respective rates were 71% and 67%. All 5 pts who progressed to AP/BC on treatment (2 on Nil300 and 3 on Nil400) were aged < 65 yrs. The frequency of grade 3/4 hematologic adverse events (AEs) was low in older pts; no pts had grade 3/4 neutropenia and only 1 older pt reported grade 3/4 thrombocytopenia in each nilotinib arm (Table). Transient, asymptomatic lipase elevations were reported in 11% and 16% of older pts treated with Nil300 and Nil400, and 7% of younger pts in each arm. Hyperglycemia occurred in 23% and 16% of older pts on Nil300 and Nil400, respectively, and 4% of younger pts in each arm; regardless of age, no pt discontinued study due to hyperglycemia. Among the 12 older pts with grade 3/4 hyperglycemia (8 on Nil300; 4 on Nil400), 9 pts had type 2 diabetes at baseline. There were no QTcF increases of > 60 msec from baseline in older pts and 3 in nilotinib-treated pts < 65 yrs old (1 on Nil300; 2 on Nil400). QTcF prolongation of > 500 msec did not occur in any pt treated with nilotinib on study. Periodic echocardiograms were done, and there were no decreases of > 15% in left ventricular ejection fraction from baseline in any pt treated with nilotinib on study. There were 4 cases of ischemic heart disease reported in older pts (1/35 [3%] on Nil300; 3/25 [12%] on Nil400) and 7 cases in pts < 65 yrs of age (4/244 [2%] on Nil300; 3/252 [1%] on Nil400). No sudden deaths occurred on study. Discontinuation occurred in approximately 25% of older and younger pts with Nil300, of which, 6% and 9%, respectively, were due to AEs/lab abnormalities. Discontinuation from study with Nil400 was 46% in older pts and 19% in younger pts; of which, 36% and 10% were due to AEs/lab abnormalities. Conclusions: Older pts treated with nilotinib demonstrated high rates of cytogenetic and molecular responses and low rates of progression. Nilotinib was generally well tolerated by older pts. In older pts, Nil300 had numerically higher rates of CCyR and MMR and was generally better tolerated (as evidenced by fewer AEs and discontinuations) vs Nil400. These data support the use of Nil300 in older pts with newly diagnosed CML-CP. Disclosures: Larson: Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Bunworasate:Novartis Pharmaceutical: Research Funding. Turkina:Novartis: Consultancy, Honoraria; BMS: Honoraria. Goldberg:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Dorlhiac-Llacer:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hochhaus:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Yu:Novartis: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Clark:Bristol Myers Squibb: Honoraria, Research Funding; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Safety and Tolerability of Plerixafor in Combination with Cytarabine and Daunorubicin in Patients with Newly Diagnosed Acute Myeloid Leukemia- Preliminary Results From a Phase I Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 82-82 ◽  
Author(s):  
Geoffrey L. Uy ◽  
David Avigan ◽  
Jorge E. Cortes ◽  
Pamela S. Becker ◽  
Robert W. Chen ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Fold Increase ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Post Induction ◽  
Experienced Grade

Abstract Abstract 82 Introduction: Plerixafor is thought to enhance chemotherapy mediated myeloid leukemia cell death by promoting mobilization from the protective bone marrow niche and disrupting CXCL12-mediated survival signals. We conducted a Phase 1, open-label, multi-center, dose escalation study in patients (pts) with newly diagnosed AML to determine the maximum tolerated dose (MTD) and safety of plerixafor when combined with cytarabine and daunorubicin. Methods: Adult pts ≤70 years old with newly diagnosed AML were eligible to participate in this ongoing study. Pts with M3 AML and those <50 years old with core binding factor leukemias were excluded. Pts received IV cytarabine 100 mg/m2/day by continuous infusion on days 1–7 and IV daunorubicin 90 mg/m2/day on days 1–3 (7+3 regimen). Plerixafor was given as a 30-min IV infusion, 4–5 hours before daunorubicin beginning on day 2, and repeated at the same time on days 3–7, starting at 0.24 mg/kg, proceeding to dose levels of 0.32, 0.40, and 0.48 mg/kg. Three to 12 evaluable pts were enrolled in each cohort in a modified 3+3 design. Pts were observed for dose-limiting toxicities (DLT) from the first plerixafor dose through day 49. Responses were assessed using IWG response criteria. Serial peripheral blood (PB) samples were analyzed before and after the first and last plerixafor doses for circulating CD34+/CD117+ leukemia cells. Results: Twenty-three pts (median age 57 years) have been enrolled in 4 cohorts. Baseline characteristics are included in Table 1. Plerixafor infusion on day 2 caused a rise in PB AML blasts (mean 3.01-fold increase) peaking at 2–4 hours after administration. On day 7, there was a mean 1.51-fold increase in PB AML blasts but far fewer total cells were detected. Eighteen (86%) pts experienced adverse events (AEs) that were reported as at least possibly related to plerixafor. The majority were Grade 1/2 in severity and mainly included gastrointestinal disorders. Four (19%) pts experienced Grade 3 plerixafor-related AEs including febrile neutropenia (n=3), neutropenia (n=1), nausea (n=1), infections (n=2) and decreased appetite (n=1) commonly observed with 7+3 regimen. One (5%) pt (0.48 mg/kg cohort) experienced Grade 4 related AEs of thrombocytopenia and asymptomatic pulmonary embolism (while receiving medroxyprogesterone); the latter was the only possibly-related SAE reported. The median time to neutrophil (≥ 0.5 × 109/L) and platelet (≥100 × 109/L) recovery for responders was 19.5 (range 13–35) and 21 (range 17–37) days, respectively. There were 4 (17%) plerixafor unrelated deaths (0.24mg/kg): 1 within 30 days post induction due to an AE of acute respiratory distress syndrome and 3 due to disease progression > 3 months post induction. No DLTs have been reported. Of 21 pts with available data, 14 (67%) had complete response (CR), 2 had CR with incomplete count recovery (CRi), 2 had residual leukemia (RL), 2 had treatment failure (TF) due to resistant disease and 1 was not evaluable (NE) due to early death. Conclusions: The toxicity or hematopoietic recovery expected with the 7+3 regimen was not significantly altered by the addition of plerixafor. Transient mobilization of AML blasts into PB was observed immediately following plerixafor treatment. Sixteen of 21 patients, majority of who had intermediate or poor risk cytogenetics, achieved a CR or CRi, with responses observed across all plerixafor doses. Twice daily plerixafor dosing and addition of G-CSF to augment mobilization are being currently explored. Disclosures: Uy: Sanofi Oncology: Consultancy, Speakers Bureau. Off Label Use: Plerixafor (Mozobil®), a hematopoietic stem cell mobilizer, is approved by the US FDA in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. Avigan:Sanofi Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes:Ariad: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chemgenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Becker:Millenium: Research Funding; Glycomimetics: Research Funding; Sanofi Oncology: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy. Hewes:Sanofi Oncology: Employment. Johns:Sanofi Oncology: Employment. Erba:Ambit: Research Funding; Ascenta: Research Funding; Celgene: Speakers Bureau; Chroma: Research Funding; Eli Lilly: Research Funding.

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 Prognostic Significance of Early Immune Reconstitution in Newly Diagnosed Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3158-3158
Author(s):  
Moritz Binder ◽  
S. Vincent Rajkumar ◽  
Martha Q. Lacy ◽  
Morie A. Gertz ◽  
Francis K. Buadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Immune Reconstitution ◽  
Immune Dysregulation ◽  
Blood Parameters ◽  
Newly Diagnosed ◽  
Advisory Committees

Abstract Background: Peripheral blood biomarkers of tumor microenvironment and immune surveillance such as absolute lymphocyte (ALC) and monocyte (AMC) counts are independent prognostic factors in several hematologic malignancies including multiple myeloma. The timing and prognostic impact of immune reconstitution has been studied after autologous hematopoietic stem cell transplantation, less is known about its significance in newly diagnosed multiple myeloma prior to transplantation. Methods: We studied 771 patients with newly diagnosed multiple myeloma who were treated with novel agents at Mayo Clinic between 01/2004 and 12/2015. Peripheral blood absolute lymphocyte and monocyte counts were measured at the time of treatment initiation and one month thereafter in all patients (including data obtained between 14 and 42 days after treatment initiation). The outcome of interest was overall survival. The peripheral blood parameters of interest were abnormal ALC (reference range 800-2400/µL) and AMC (reference range 500-1500/µL) at baseline and at one month. Immune dysregulation was defined as both abnormal ALC and AMC. Immune reconstitution was defined as recovery of both normal ALC and AMC. The Wilcoxon signed-rank test was used to compare the peripheral blood parameters before and after the first month of treatment. Multivariable-adjusted proportional hazards regression models were used to assess the associations between changes in peripheral blood parameters and overall survival. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis was 65 years (27 - 90) and 459 patients were male (60%). The three most common first-line regimens were lenalidomide + dexamethasone, bortezomib + cyclophosphamide + dexamethasone, and bortezomib + lenalidomide + dexamethasone. Two hundred and eighty patients (36%) went on to undergo autologous hematopoietic stem cell transplantation as part of their first-line therapy. The median ALC decreased from 1100/µL (range 60 - 5590) at baseline to 850/µL (range 60 - 5590) at one month (p < 0.001). The median AMC increased from 330/µL (range 0 - 1840) at baseline to 420/µL (range 0 - 1840) at one month (p < 0.001). The median time between re-assessment of ALC and AMC was 25 days (range 15 - 42). Two hundred and thirty-four patients (31%) had evidence of immune dysregulation at baseline (both abnormal ALC and AMC). Eighty-seven of these 234 patients (37%) recovered normal ALC and AMC at one month (early immune reconstitution). One hundred and thirty-seven of the 537 patients with normal ALC and AMC at baseline (26%) developed new immune dysregulation at one month. The absence of immune dysregulation at baseline (compared to the presence thereof) was associated with better overall survival (HR 0.77, 95% CI 0.61 - 0.97, p = 0.025, n = 771). The absence of immune dysregulation at one month (compared to the persistence or development thereof) was associated with better overall survival (HR 0.63, 95% CI 0.50 - 0.80, p < 0.001, n = 771). Early immune reconstitution (compared to the persistence or development of immune dysregulation) was associated with better overall survival (HR 0.62, 95% CI 0.43 - 0.92, p = 0.016, n = 771). Both associations remained statistically significant after adjusting for age at diagnosis, sex, International Staging System stage, and eligibility for transplantation: HR 0.70 (95% CI 0.54 - 0.90, p = 0.006, n = 612) and HR 0.59 (95% CI 0.39 - 0.90, p = 0.014, n = 612), respectively. Conclusions: Peripheral blood biomarkers of immune dysregulation vary over time and have prognostic significance both at baseline and during follow-up. The presence or development of immune dysregulation in newly diagnosed multiple myeloma is an independent risk factor. The favorable impact of early immune reconstitution suggests that immune dysregulation is a potentially modifiable risk factor that may be exploited for therapeutic benefit. Figure. Figure. Disclosures Lacy: Celgene: Research Funding. Gertz:celgene: Consultancy; Medscape: Consultancy; janssen: Consultancy; Prothena: Honoraria; Apellis: Consultancy; Ionis: Honoraria; annexon: Consultancy; spectrum: Consultancy, Honoraria; Amgen: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Consultancy; Research to Practice: Consultancy; Teva: Consultancy; Alnylam: Honoraria. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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