MDS with Isolated Trisomy 8. a Type of MDS Frequently Associated with Myeloproliferative Features? A Report from the GFM

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2881-2881
Author(s):  
Louis Drevon ◽  
Alice Marceau ◽  
Virginie Eclache ◽  
S. Dominique Raynaud ◽  
Valentine Richez ◽  
...  
Keyword(s):  
Research Funding ◽  
Trisomy 8 ◽  
Advisory Committees ◽  
Hypercellular Marrow ◽  
Diagnostic Samples ◽  
Small Patient ◽  
The Difference ◽  
Wbc Count ◽  
Very High

Abstract Introduction Isolated trisomy 8 is a frequent cytogenetic abnormality in MDS, but hematological characteristics of MDS with isolated trisomy 8 have not been reported in detail. Patients and Methods This was a retrospective analysis of cases of MDS with isolated trisomy 8 diagnosed in 6 French centers of the Groupe Francophone des Myélodysplasies (GFM) between 2003 and 2013. Only patients with isolated trisomy 8 diagnosed as MDS or MPN/MDS (other than CMML) according to WHO were eligible, excluding AML, well characterized MPN (PV, ET) and CMML. Myeloproliferative (MP) features were defined by repeated presence (in the absence of infection) of one of the following: WBC > 10G/L, circulating immature granulocytes (myelemia ) > 2%, or palpable splenomegaly. Results 103 patients with isolated trisomy 8 were identified, with a median age of 75 years, and M/F 1.7. At diagnosis, median WBC count was 4.1 G/L, with WBC ≥ 10 G/L in 13 patients (12.6 %), myelemia ≥ 2% in 27 patients (26.2 %), palpable splenomegaly in 9 patients (8.7 %). WHO diagnosis included 20 RA, 2 RARS, 22 RCMD, 1 RCMD-RS, 1 RCUD, 21 RAEB-1, 18 RAEB-2, 7 MDS-U, 10 MDS/MPN, 1 hypoplastic MDS. IPSS was intermediate 1 (72.2 %), intermediate 2 (19.6 %), high (8.2 %) ; IPSS-R was low (37.1 %), intermediate (29.9 %), high (22.7 %), very high (10.6 %). MP features were found in 50 patients (48.5 %): 31 at diagnosis, 19 during evolution (in patients without MP features at diagnosis). Bone marrow morphological features could be reviewed in 15 MP cases, showing hypercellular marrow in 60 % cases, granulocytic hyperplasia (E/G<0.25) in 53%, marked neutrophil hypogranularity in 87% and abnormal chromatin clumping in neutrophils in 53 %. Somatic mutations were studied in 31 patients on diagnostic samples (16 MP and 15 non MP) for 27 most frequently mutated genes in MDS and MPN: ASXL1, CBL, DNMT3A, ETV6, EZH2, IDH1, IDH2, JAK2, cKIT, KRAS, NRAS, MPL, PHF6, PTPN11, RIT, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1, WT1, ZRSR2, FLT3-TKD, FLT3-ITD, NPM1 (FLT3-TKD, FLT3-ITD and NPM1 were studied in only 15 patients). Mutations were seen, for MP cases, in ASXL1 (64%), EZH2 (50%), TET2 (40%), RUNX1 (33%), SRSF2 (27%), DNMT3A (15%), JAK2 (14%), IDH2 (14%), NRAS (8%), SF3B1 (9%), U2AF1 (8%); for non MP cases in ASXL1 (33%), SRSF2 (27%), SF3B1 (27%), TET2 (20%), DNMT3A (13%), JAK2 (13%), RUNX1 (13%), EZH2 (7%), IDH2 (7%), ZRSR2 (7%), NRAS (0%). In spite of a trend for more mutations of ASXL1 (p=0.128), and EZH2 (p=0.053) in MP forms, the difference with non MP forms was not significant, possibly due to small patient numbers. 40 patients received an HMA (AZA in 36, DAC in 4) and 27.3% responded (4 CR, 1 PR, 1 marrow CR, 3 HI), including 11.7% of MP cases and 43.8% of non MP cases (p=0.057). 5 patients received intensive chemotherapy (with 2 CR). 42 (40.8%) received an ESA, with 60% responses, including 50% in MP and 73% in non MP patients (p= NS).10 (9.7%) received hydroxyurea. With a median follow up of 30 months, progression to AML was seen in 26% and 18.9% in MP and non MP patients, respectively (p= NS). Median survival was 35 months in the whole cohort, without difference between patients who, at diagnosis had MP features and no MP features (35 months for both). Conclusion Myeloproliferative (MP) features were found at diagnosis or during evolution in our experience in about 50% of MDS with isolated trisomy 8, a finding not previously reported, to our knowledge, and suggesting that some of those patients may have to be reclassified among MDS/MPN. The subset of patients with MP features tended to have a higher frequency of ASXL1 and EZH2 mutations (findings that will have to be confirmed on larger patient numbers), and seemed to respond poorly to HMA, although its survival was not lower than that of non MP forms in our experience. Disclosures Park: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Celgene: Research Funding. Fenaux:AMGEN: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding.

Switching to Nilotinib Is Associated with Continued Deeper Molecular Responses in CML-CP Patients with Minimal Residual Disease After ≥ 2 Years On Imatinib: Enestcmr 2-Year Follow-up Results

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 694-694 ◽  
Author(s):  
Timothy P. Hughes ◽  
Jeffrey H. Lipton ◽  
Nelson Spector ◽  
Brian Leber ◽  
Ricardo Pasquini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Minimal Residual Disease ◽  
Research Funding ◽  
Residual Disease ◽  
Molecular Response ◽  
Advisory Committees ◽  
Molecular Responses ◽  
The Difference ◽  
Minimal Residual

Abstract Abstract 694 Background: Superior rates of deeper molecular responses were achieved with nilotinib vs imatinib in patients newly diagnosed with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials—newly diagnosed patients (ENESTnd) trial. In addition, the 12-month (mo) analysis of the ENEST—complete molecular response (ENESTcmr) study demonstrated that switching to nilotinib after a minimum of 2 years on imatinib led to increased rates of major molecular response (MMR) and deeper molecular responses vs remaining on imatinib. Results from ENESTcmr are presented here with minimum 24 mo of patient follow-up. Methods: Patients with Ph+ CML-CP who had achieved complete cytogenetic responses but still had persistent BCR-ABL positivity by real-time quantitative polymerase chain reaction (RQ-PCR) after ≥ 2 years on imatinib were eligible. Patients (n = 207) were randomized to switch to nilotinib 400 mg twice daily (BID; n = 104) or to continue on the same dose of imatinib (400 or 600 mg once daily [QD]; n = 103). Rates of MMR, MR4 (BCR-ABL ≤ 0.01% according to the International Scale [IS], corresponding to a 4-log reduction), MR4.5 (BCR-ABL ≤ 0.0032%IS, corresponding to 4.5-log reduction), and undetectable BCR-ABL via RQ-PCR with ≥ 4.5-log sensitivity were measured. Results: Among all randomized patients (intent-to-treat population), significantly more patients treated with nilotinib continued to achieve undetectable BCR-ABL by 24 mo (32.7% on nilotinib vs 16.5% on imatinib; P =.005; Table).The difference between the arms in achievement of this endpoint increased between 1 and 2 years (from 12.4% to 16.2%). The median time to MR4.5 and undetectable BCR-ABL was also significantly faster on nilotinib than on imatinib (P = .005 and .003, respectively). Cumulative rates of MR4.5 and undetectable BCR-ABL continued to be higher with nilotinib in patients without those responses at baseline, and the difference between arms appeared to increase over time. The safety profiles for nilotinib and imatinib were consistent with prior studies. By 24 mo, no patients in either arm progressed to accelerated phase/blast crisis. No patients on nilotinib died since the 12-mo analysis; 1 patient on imatinib died from metastatic prostate cancer in follow-up after discontinuation from the study. Conclusions: Switching to nilotinib led to significantly faster, deeper molecular responses in patients with minimal residual disease on long-term imatinib therapy. Since the 12-mo analysis, rates of deep molecular response (MR4.5 and undetectable BCR-ABL) have remained significantly higher in patients who did not have the response at baseline and were switched to nilotinib (vs those remaining on imatinib). In fact, the difference in favor of nilotinib increased between 1 and 2 years. These results suggest that switching to the more potent, selective tyrosine kinase inhibitor nilotinib is beneficial in patients with minimal residual disease after long-term imatinib therapy. Achievement of these deeper molecular responses (MR4.5 and undetectable BCR-ABL) after switching to nilotinib may enable a greater proportion of CML-CP patients to be eligible for future discontinuation studies. Cumulative rates of confirmed undetectable BCR-ABL by 24 mo will be presented as the confirmation assessments for several responders were not available at the time of this analysis. Disclosures: Hughes: Novartis Pharmaceuticals Corp: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy; CSL: Research Funding. Lipton:Novartis: Consultancy, Research Funding, Speakers Bureau. Spector:Novarits: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy. Leber:Novartis: Advisory Board Other, Honoraria, Speakers Bureau. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Etienne:Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Purkayastha:Novartis Pharmaceuticals Corp: Employment. Collins:Novartis Pharmaceuticals Corp: Employment. Szczudlo:Novartis Pharmaceuticals Corp: Employment. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Enestnd 4-Year (y) Update: Continued Superiority of Nilotinib Vs Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome–Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1676-1676 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Dong-Wook Kim ◽  
Surapol Issaragrisil ◽  
Richard E Clark ◽  
Josy Reiffers ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Standard Of Care ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Molecular Responses ◽  
The Difference ◽  
The Impact

Abstract Abstract 1676 Background: Pts treated with nilotinib in the ENESTnd phase 3 trial achieved higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular responses (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), significantly lower rates of progression to accelerated phase/blast crisis (AP/BC), and fewer CML-related deaths compared with imatinib by 1, 2, and 3 y. Here, we report data with a minimum follow-up of 3 y; efficacy and safety data based on longer follow-up of 4 y will be presented to further assess the impact of nilotinib vs imatinib in pts with newly diagnosed Ph+ CML-CP. Methods: Adult pts (N = 846) with newly-diagnosed Ph+ CML-CP were randomized to nilotinib 300 mg twice daily (BID; n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg once daily (QD; n = 283). MMR, MR4, MR4.5, time to progression to AP/BC, progression-free survival (PFS), and overall survival (OS) were evaluated. Results: Significantly higher rates of MMR, MR4, and MR4.5 by 3 y were achieved in nilotinib- vs imatinib-treated pts (Table). Nilotinib led to the achievement of higher rates of molecular responses regardless of Sokal risk group or age. The difference in the rates of both MR4 and MR4.5 continued to be significantly higher for nilotinib, with the difference in favor of nilotinib increasing from 1 to 3 y (MR4: 9%-14% difference by 1 y, 18%-24% difference by 3 y; MR4.5: 6%-10% difference by 1 y, 13%-17% difference by 3 y). Among patients who achieved MMR, more pts achieved MR4 or MR4.5 on nilotinib 300 mg BID (68%) and nilotinib 400 mg BID (62%) compared with imatinib (49%). No pt in any arm progressed after achieving MR4.5. Significantly fewer pts progressed to AP/BC on nilotinib vs imatinib (Table). No new progressions occurred on core treatment between the 2-y and 3-y analyses. When events occurring after treatment discontinuation were included, the rates of progression to AP/BC were also significantly lower with nilotinib vs imatinib (Table). Nearly twice as many pts had emergent mutations on imatinib (n = 21) vs either nilotinib arm (n = 11 in each arm), with 5 pts overall developing mutations between 2 and 3 y. OS remained similar in all groups at 3 y, but fewer CML-related deaths occurred in both the nilotinib 300 mg BID (n = 5) and 400 mg BID (n = 4) arms vs imatinib (n = 14). Both drugs were well tolerated. Few new adverse events (AEs) and laboratory abnormalities were observed between 2 and 3 y. Rates of discontinuation due to AEs were 10%, 14%, and 11% in the nilotinib 300 mg BID, nilotinib 400 mg BID, and imatinib arms, respectively. Conclusions: Nilotinib continues to demonstrate superiority vs imatinib, yielding faster and deeper molecular responses and a significantly decreased risk of progression. Results of ENESTnd support the use of nilotinib as a standard of care option in newly diagnosed adult pts with Ph+ CML-CP and should be considered to replace imatinib as the standard-of-care frontline therapy for patients with Ph+ CML-CP. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Kim:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Research Funding; II-Yang: Research Funding. Clark:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Reiffers:BMS: Expense reimbursement for travel expenses Other; Novartis: Expense reimbursement for travel expenses, Expense reimbursement for travel expenses Other. Nicolini:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria. Hughes:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Hochhaus:BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Kemp:Novartis Pharmaceuticals Corp: Employment. Fan:Novartis Pharmaceuticals Corp: Employment. Waltzman:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Larson:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding.

scholarly journals Use of Artificial Intelligence Electrocardiography to Predict Atrial Fibrillation (AF) in Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 50-51
Author(s):  
Georgios Christopoulos ◽  
Zachi I. Attia ◽  
Peter A. Noseworthy ◽  
Timothy G. Call ◽  
Wei Ding ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
High Risk ◽  
Sinus Rhythm ◽  
Board Of Directors ◽  
Research Funding ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Increased Risk ◽  
Very High

Background: Clinical factors including previous history of AF, heart failure, hypertension, valvular heart disease, increased age and male gender increase the risk of AF in CLL patients (Shanafelt, Leukemia and Lymphoma 2017). Treatment with Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib has also been associated with an increased risk of AF in CLL. We evaluated the role of artificial intelligence electrocardiography (AI-ECG) in predicting ibrutinib-induced AF (and, for reference, AF unrelated to ibrutinib) in patients with CLL. Methods: We identified two cohorts of CLL patients using the Mayo Clinic CLL Database. Cohort 1 included patients evaluated within 12 months of CLL diagnosis who did not ever receive ibrutinib. Cohort 2 included patients who were treated with ibrutinib. The electrocardiographic signature of AF in sinus rhythm was detected by an AI-ECG algorithm previously developed using a convolutional neural network (Attia, Lancet 2019). The baseline AI-ECG AF score (positive defined as &gt;0.10 on a scale of 0-1 which offers best balance between sensitivity and specificity per Attia et al.) was computed based on ECGs obtained within 10 years prior to CLL diagnosis (Cohort 1) or 10 years prior to initiation of ibrutinib therapy (Cohort 2). Patients with AF at baseline, missing data, or with ECGs previously used to train the AI algorithm were excluded. Reverse Kaplan Meier diagrams were plotted for both cohorts grouped by AI-ECG positivity. Cox proportional hazards were fitted to assess the predictive ability of AI-ECG in both cohorts. Results: After screening 2,739 patients and applying exclusion criteria (126 patients had baseline AF) a total of 1,149 patients with median 4 (interquartile range [IQR] 2-9) baseline ECGs were included in the analysis (Figure 1A). Cohort 1 included 951 patients with a median follow up of 3.0 (IQR 0.6-7.0) years and positive baseline AI-ECG in 546 (57%) patients. Cohort 2 included 198 patients with a median follow up of 1.6 (IQR 0.7-3.2) years and positive baseline AI-ECG in 91 (46%) patients. In Cohort 1, the median age was 67 years (IQR 58-72), 681 (72%) of patients were men, 68% had low/intermediate risk CLL-International Prognostic Index (IPI), and 32% had high/very high-risk CLL-IPI. In Cohort 2, the median age was 69 years (IQR 62-75), 139 (70%) of patients were men, 13% had low/intermediate risk CLL-IPI, and 87% had high/very high-risk CLL-IPI. AF occurred during follow up in 164 patients (17%) in Cohort 1 and 46 patients (23%) in Cohort 2. In both Cohorts 1 and 2, a positive baseline AI-ECG significantly increased the incidence of AF during follow up (log rank &lt;0.001) (Figure 1B and C). Hazard ratios (for positive vs. negative AI-ECG) were 33.9 (95% confidence interval [CI] 15.0-76.6) for Cohort 1 and 14.8 (95% CI 5.3-41.3) for Cohort 2. Conclusion: The addition of AI to a standard 12-lead ECG obtained during normal sinus rhythm - an inexpensive and ubiquitous test - predicts the occurrence of future AF in patients with CLL. This holds true irrespective of BTKi -based therapy and has important implications for the management of CLL patients. Disclosures Ding: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Astra Zeneca: Research Funding; Abbvie: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees. Kenderian:BMS: Research Funding; Gilead: Research Funding; Novartis: Patents & Royalties, Research Funding; Mettaforge: Patents & Royalties; Juno: Research Funding; MorphoSys: Research Funding; Lentigen: Research Funding; Sunesis: Research Funding; Tolero: Research Funding; Kite: Research Funding; Humanigen: Consultancy, Patents & Royalties, Research Funding; Torque: Consultancy. Wang:Novartis: Research Funding; Innocare: Research Funding; Incyte: Research Funding. Kay:Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Abbvie: Research Funding; MEI Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Cellectar: Consultancy; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Celgene: Honoraria; GlaxoSmithKline: Research Funding. Parikh:MorphoSys: Research Funding; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; Verastem Oncology: Honoraria; GlaxoSmithKline: Honoraria; TG Therapeutics: Research Funding; Pharmacyclics: Honoraria, Research Funding.

scholarly journals Patients with Unexplained Thrombosis Require a Prompt Investigation to Search a Chronic Myeloproliferative Neoplasm (MPN), Even If Platelet Count Is <600x109/L. Analysis on 129 Patients from Registro Italiano Trombocitemie (RIT)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5181-5181
Author(s):  
Giulia Benevolo ◽  
Alessandra Iurlo ◽  
Gabriele Gugliotta ◽  
Alessia Tieghi ◽  
Gianluca Gaidano ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Advisory Committees ◽  
Thrombotic Risk ◽  
Cytoreductive Treatment ◽  
Wbc Count

Abstract Background In patients with Ph-negative MPN, a prior thrombosis (PrTh) occurs in around 1/5 of cases, with variable platelet (PLT) count and variable distance from diagnosis. Objective To investigate the influence of PLT count at PrTh on diagnostic and therapeutic approach in MPN patients. Material and methods We evaluated 129 MPN patients from RIT, reclassified according to WHO 2008 criteria as ET (n70), initial-primary myelofibrosis (n29), early-PV (n10), and unclassifiable-MPN (n20). Results Patients, 60 males and 69 females, showed following PrTh: 91(71%) major arterial (37 AMI, 4 angina, 24 stroke, and 26 TIA); 12(9%) minor arterial; 22(17%) major venous (8 DVT, 7 splanchnic, 4 cerebral sinus, 3 pulmonary embolism); and 4(3%) minor venous events. PrTh occurred at a median distance of 4.1 months (range 0.1-118) from MPN diagnosis. This distance was >24 months in 21(16%) patients. At occurrence of PrTh, median age was 58 years. PLT count (x109/L) had a median value of 661 (range 150-2200), and was ≤450, 451-600, 601-700, 701-1000, and >1000 in 15(12%), 35(27%), 26(20%), 43(33%), and 10(8%) patients, respectively. Median white blood cell (WBC) count was 9.0 x 109/L and median hematocrit (HCT) value was 46% in males, and 41% in females. Median time (months) from PrTh to diagnosis of MPN was higher (p0.004) in patients with lower PLT count (x 109/L): ≤450 (50.2), 451-600 (11.7), 601-700 (2.7), 701-1000 (1.8), and >1000 (1.4). After occurrence of PrTh, all patients received conventional anti-thrombotic treatment, but in 7(5.4%) patients 9 recurrent thrombosis were reported before MPN diagnosis (11/100 pt-years). At MPN diagnosis, clonality was documented in 101(78%) patients (JAK2 V617F mutation in 96 cases, 74%). The age was >60 years in 61(47%) patients. PLT count (x109/L) had a median value of 720 (166-2440), and was ≤450 (n 7, 5%), 451-600 (n 21, 16%), 601-700 (n 28, 22%), 701-1000 (n 58, 45%), >1000 (n15, 12%). WBC count (109/L) had a median value of 8.9, and was >10 in 40 (31%) cases. Median HCT level (%) was 45.6 in males and 42.1 in females. Cardiovascular risk factors (CVRF), comorbidities and symptoms were documented in 103(80%), 97(75%), and 57(44%) cases, respectively. Thrombotic risk (IPSET-Th) was high in 97.5%, and intermediate in 2.5% of cases. All 129 patients received anti-thrombotic drugs (low dose aspirin in 95% of cases) and, immediately after the diagnosis, they started a cytoreductive treatment (hydroxycarbamide 89%, anagrelide 8%, interferon-alpha 3%). Patients with a PLT count (x109/L) at PrTh ≤600(n 50), as compared with those with a PLT count >600(n 79), showed a longer median time to the MPN diagnosis (16.7 vs 2.0 months, p<0.001). No significant difference was found in the rate of: arterial PrTh (80% vs 79.7%, p0.97); recurrence of thrombosis before the diagnosis (8% vs 4%, p0.69); JAK2 V617F mutation (80% vs 71%, p0.29); age >60 years (52% vs 44%, p0.39); CVRF (82%vs79%, p0.63); WBC >10 x109/L (23% vs 39%, p0.07); HCT high level [>47% in males, >44% in females](28% vs 36%, p0.37), and high thrombotic risk [IPSET-Th] (96%vs99%, p0.56). During follow-up (median 7.9 years) they showed a higher incidence of thrombosis recurrence (30%vs15%, p0.04; 4.5 vs 1.7/100 pt-y, p<0.01) Conclusion Time to MPN diagnosis was significantly longer in patients with PLT count (x109/L) at PrTh ≤600 vs >600, and this time to diagnosis was characterized by a not negligible thrombosis recurrence. Moreover, during follow-up they showed a higher incidence of thrombosis recurrence. This analysis strongly suggests that a PLT count <600 or even <450 x109/L, in patients with unexplained thrombosis, deserves the search of a probable MPN, in order to promptly start cytoreductive treatment in addition to a conventional anti-thrombotic therapy. Disclosures Passamonti: Novartis: Consultancy, Honoraria, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees.

Genetic Response to Lenalidomide in the Circulating Progenitor Cell Compartment of MDS Cohort. Preliminary Results of the Multicenter German LE-MON-5 Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1721-1721
Author(s):  
Katayoon Shirneshan ◽  
Ulrich Germing ◽  
Friederike Braulke ◽  
Julie Schanz ◽  
Uwe Platzbecker ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Response To Therapy ◽  
Fish Analysis ◽  
Trisomy 8 ◽  
Advisory Committees ◽  
Clone Size ◽  
Observation Period

Abstract Abstract 1721 Introduction: LE-MON-5 is a multicenter German phase-II study to verify the safety of monotherapy with lenalidomide (LEN) in MDS patients (pts) with IPSS low or Int-1 and isolated del(5q). We report our cytogenetic results after a monitoring period of sixteen months since start of the trial. Methods: For sequential and frequent survey of LEN-treated pts we applied FISH on enriched CD34+ stem cells from peripheral blood (CD34+ pb) every 2–3 months using a panel of 8 to 13 probes. Karyotyping and FISH on bone marrow aspirates was performed at initial screening and every six months. The median number of analyzed metaphases was 25 (4–30) and FISH analyzing was based on 200 interphase nuclei. Results: We have already screened 94 pts and could confirm isolated del(5q) in 76 (81%). Due to our cytogenetic results demonstrating additional changes in 18/94 (19%) pts, these were registered as screening failures and thus excluded from the study. Until now cytogenetic follow-up data for 40 pts is available. After a median follow-up of 9 months (2–16 months) we have observed a significant impact of LEN on the reduction of the clone size (p < 0.05) by FISH-monitoring. Based on cytogenetic remission, we have separated the cohort into three groups: Fast responders (14/40 (35%) pts) showed a very rapid cytogenetic response to therapy with >50% reduction of 5q- clone size within two months. In the second group, the slow responders, we observed >50% reduction of clone size in 9/40 (22.5%) after > two months. However, two pts showed an increase of 5q- clone after 12 and 13 months respectively after initial response in the sense of a relapse. In the third group, the non responders, (11/34 (27.5%)) we could not observe any cytogenetic response during the as yet limited observation period. In six cases (15%) we detected a reduction of the 5q- clone during follow-up, but the emergence of additional aberrations were also observed such as: 1. trisomy 8 in 6.7% of metaphases after 8 months and is reduced to 3.6% after 12 months, 2. trisomy 4 in 6.7% of metaphases after 6 months and is disappeared after 12 months, followed by emergence of trisomy 8 in 8% of interphase cells, 3. finally, two cases showed loss of Y-chromosome after 4 months in 6% and 19% of CD34+ pb cells, respectively. In CD34+ pb cells of another case, trisomy 8 was detectable after two months in 3.5% of cells. All these new secondary abnormalities occurred in cells with normal chromosomes 5 and were slightly above or below our laboratory thresholds (3 times standard variation). In only one case, a new abnormality emerged in the 5q- clone: In this case additional del(20q) occurred after 2 months in 46% of CD34+ pb cells. In this case no reduction of 5q- cells after 4 months of treatment was observed. However, FISH analysis after 6 months of treatment showed a 14% reduction for both aberrations. To date we could not identify any pts who acquired complex anomalies while treated with LEN. Conclusion: FISH analysis of CD34+ pb cells allows a reliable frequent and relevant genetic monitoring of treatment response to LEN. Our results confirm the positive and rapid effects of LEN on clones with del(5q): Thus, already after 2 months, we could observe up to 90% reduction in the 5q- clone size in 35% of pts. In general, remission rates increased with duration of therapy. We suspect that trisomy 4, 8 and Y-loss are fluctuant “mini clones” without any clinical relevance. Inclusion of additional pts and prolonged observation period will help us to better evaluate the clinical response to LEN. Disclosures: Off Label Use: lenalidomide for MDS del(5q) provided by Celgene for this clinical study. Germing:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Braulke:Celgene: Honoraria, Research Funding. Schanz:Celgene: Honoraria, Research Funding. Giagounidis:Celgene: Honoraria. Götze:Celgene: Honoraria. Haase:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Evaluation of Cytogenetic Stratifications in Myelofibrosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1763-1763
Author(s):  
Lucia Masarova ◽  
Prithviraj Bose ◽  
Naveen Pemmaraju ◽  
Zeev E. Estrov ◽  
Lingsha Zhou ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Chromosome 1 ◽  
Trisomy 8 ◽  
Advisory Committees ◽  
High Risk Patients ◽  
Single Deletion ◽  
Risk Patients ◽  
Very High

Abstract Introduction: The revised cytogenetic risk stratification of patients with primary myelofibrosis (PMF) divided patients into 3 prognostic categories, with additional new category of very high risk patients (VHR). This score should enhance traditional classification incorporated in the Dynamic International Prognostic Scoring System-Plus (DIPPS-Plus). Objective: To evaluate the prognostic utility of cytogenetic stratifications (DIPSS-Plus and the revised cytogenetic model) in patients with PMF referred to our institution between 1984 and 2016. Methods: We retrospectively reviewed the charts of 883 patients with PMF with available cytogenetic analysis at the time of referral to our institution (> 10 metaphases). Cytogenetic was reported according to the International System for Human Cytogenetic Nomenclature. Patients were classified into cytogenetic risks based on DIPSS-Plus (Gangat, JCO, 2011), and the revised cytogenetic model (Tefferi, Leukemia, 2017). Overall survival (OS) was estimated using the Kaplan-Meier method, and groups were compared by the log rank test. Impact of cytogenetic abnormalities on OS was also evaluated by comparing them against patients with diploid karyotype using stepwise Cox regression. Results: Median age was 66 years (range, 27-88), and 64% of patients were male. The distribution of DIPSS scores was as follows: 8% low, 48% intermediate 1, 44% intermediate 2 and 14% high. OS in each DIPSS category was 53, 46, 26, 15 months (p<0.001). The JAK2, MPL and CALR mutation was present in 55% (n=486), 6% (n=50), and 7% (n=64). Overall, 563 (64%) patients had diploid karyotype. The most frequent abnormal karyotypes were single 20q- (n=68, 8%), single 13q- (n=40, 4.5%), and ≥3 abnormalities (Abn; complex karyotype, CK, n=52, 6%). Among patients with CK, 27 (52%) pts had VHR Abn. After a median follow-up of 22.4 months (range, 0.5-251); 708 (80%) of patients died. Eighty five patients (10%) developed acute leukemia, 39% of these patients had CK. According to DIPSS-plus, patients were stratified into favorable (FAV, n=758, 86%) and unfavorable (UNF, n=126, 14%) category with distinct median OS of 35 months (range, 31-39), and 17 months (range, 11.6-22), p < 0.001 (HR 1.37, [95% CI 1.11-1.7]). Three year OS was 49% and 32%, respectively (Figure 1a). The revised cytogenetic stratification classified patients into favorable (n=687, 78%), unfavorable (n=151, 17%), and VHR (n=47, 5%) with respective OS of 35, 32 and 10 months (overall p<0.001, FAV vs UNF p= 0.8; Figure 1b); similar between patients in favorable and unfavorable groups. Three year OS for each group was 49%, 46% and 12%, respectively. OS of patients with individual cytogenetics (as used in the revised classification) is depicted in Table. Patients with single deletion 13q have significantly inferior OS than the remaining patients in FAV group. Patients with sole abnormality of chromosome 1 and trisomy 9 had the longest OS within the FAV group, but without reaching a statistical significance. Similarly, patients with sole trisomy 8, sole deletion 7q/5q, and other sole Abn not included elsewhere, had inferior OS when compared to the remaining patients in UNF group (Table 1). After re-grouping patients with different OS from FAV and UNF groups, we have noticed an intermediate group of patients containing the above mentioned Abn with distinctly different OS from FAV and UNF group of 24 months (range, 14.5-33; Figure 1c). Conclusions: Results from our cohort of 883 PMF patients did not confirm better discriminatory power of revised cytogenetic stratification model when compared to the DIPSS-Plus, as it failed to differentiate different OS between favorable and unfavorable groups. In our cohort, patients with single deletion 13q, single trisomy 8, and abnormalities of 5q/7q have superior OS to very high risk patients, but inferior to all remaining patients. Because the revised cytogenetic stratification has been already incorporated into newer complex molecular prognostic models of patients with PMF (MIPSSversion2.0, GIPSS), its further validation is warranted. Table Abbr.: Chr, chromosome, del, deletion, DUP, duplication, transl, translocation, excl, excluding; ¥OTHER solo: INV(9) in [3], Abn chr. 11, 12, 16, 17, 18 (mostly deletion of p/q arms, or addition) [7]; VHR = very high risk (-7; inv(3)/3q21; i(17q); 12p-/12p11.2; 11q-/11q23; autosomal trisomies excl. +8/+9). Disclosures Bose: Incyte Corporation: Honoraria, Research Funding; CTI BioPharma: Research Funding; Astellas Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; Celgene Corporation: Honoraria, Research Funding; Blueprint Medicines Corporation: Research Funding. Pemmaraju:plexxikon: Research Funding; cellectis: Research Funding; Affymetrix: Research Funding; daiichi sankyo: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; SagerStrong Foundation: Research Funding. Cortes:novartis: Research Funding. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Quality-Adjusted Survival (Q-TWiST) Analysis to Assess Benefit-Risk of Acalabrutinib Versus Idelalisib/Bendamustine Plus Rituximab or Ibrutinib Among Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3722-3722
Author(s):  
John F. Seymour ◽  
Priyanka Gaitonde ◽  
Ugochinyere Emeribe ◽  
Ling Cai ◽  
Anthony R. Mato
Keyword(s):  
Disease Progression ◽  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Publicly Traded ◽  
Advisory Committees ◽  
The Difference ◽  
Grade 3 ◽  
Definition Of

Abstract Background: Acalabrutinib (Acala) is a next-generation, highly selective, covalent BTK inhibitor (BTKi) approved for the treatment of CLL. The phase 3 ASCEND study demonstrated significant progression-free survival (PFS) benefit with Acala vs investigator's choice of chemoimmunotherapy (bendamustine + rituximab [BR]) or pi3K inhibitor (idelalisib) + rituximab (IR) in R/R CLL patients (pts) (Ghia et al. J Clin Oncol. 2020). In ELEVATE-RR, Acala demonstrated non-inferior PFS vs a first-generation BTKi (ibrutinib [Ibr]) in R/R CLL pts with high-risk genomics (Byrd et al. J Clin Oncol. 2021). Acala was well tolerated in both trials. Quality-adjusted Time Without Symptoms and Toxicity (Q-TWiST) analysis balances risks (toxicity) and benefits (prolonged survival without symptoms of disease progression or adverse events [AEs]) of oncology treatments. We conducted a Q-TWiST analysis using data from these trials to assess risk-benefit of Acala vs comparators among R/R CLL pts. Methods: Patient survival time with 16 months (ASCEND) and 41 months (ELEVATE-RR) of median follow-up data were partitioned into 3 states: time with toxicity before disease progression (TOX); time without progression or toxicity (TWiST); and time from disease progression until death or end of follow-up (relapse [REL]). Toxicity was defined as grade 3/4 AEs and, for the comparison vs Ibr, an additional definition of toxicity included AEs of any grade with frequency ≥10% (AE ≥10%). Sensitivity analyses with toxicity defined as grade 2-4 AEs will be presented. Kaplan-Meier survival curves were constructed for TOX, PFS, and overall survival (OS). For the TOX curve, event time for each pt was calculated by summing days with AEs (per toxicity definition) before disease progression, with no pt censored. Restricted means were calculated for the longest PFS time among treatment arms. Restricted mean TWiST duration was estimated using the difference between restricted means of PFS and TOX. Restricted mean REL duration was estimated using the difference between restricted means of OS and PFS. Q-TWiST was calculated by summing weighted restricted mean durations of TOX, TWiST, and REL. Utility of 1.0 for TWiST and 0.5 for TOX and REL (Gelber et al. Am Statistician. 1995) were applied. Sensitivity analysis was conducted using utility measures from trial data. Two-sided p&lt;0.05 indicated statistical significance. Results: Among Acala vs IR/BR-treated pts, significantly longer duration of TWiST (mean diff, 3.58 months [95% CI, 2.42, 4.74]) and shorter duration of REL (mean diff, −2.51 months [95% CI, −3.50, −1.60]) and TOX (mean diff, −0.73 months [95% CI, −1.24, −0.24]) were found, indicating Acala vs IR/BR-treated pts had longer time without disease progression and toxicity and shorter time with toxicity. Q-TWiST was significantly different (1.96 months [95% CI, 1.13, 2.81]) between Acala (17.48 months) and IR/BR (15.52 months). In the Acala and Ibr comparison, differences in durations of TWiST and TOX varied based on the toxicity definition while the difference in REL durations remained consistent (mean diff, 0.37 months [95% CI, −1.82, 2.60]; p=0.33]). With the toxicity definition of AE ≥10%, Q-TWiST was significantly different (2.56 months [95% CI, 0.19, 4.83]) for Acala (33.02 months) vs Ibr (30.46 months). When toxicity was defined as grade 3/4 AEs, Q-TWiST had higher estimates for Acala but the difference was not statistically significant (1.28 months [95% CI, −1.34, 3.80]). In the sensitivity analysis, Q-TWiST gains were not statistically significant, most likely because the study was not designed to collect EQ-5D data post-treatment discontinuation. Conclusions: Q-TWiST analyses integrate efficacy, safety, and quality of life into a more appropriate measure useful for detailed benefit-risk assessment of cancer treatment. This analysis demonstrated that Acala treatment is significantly superior to IR/BR treatment. Quality-adjusted survival gains of Acala over Ibr varied by toxicity definition, but was numerically higher for Acala. Overall, Acala demonstrated a favorable benefit-risk profile vs different comparators in R/R CLL. Figure 1 Figure 1. Disclosures Seymour: Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gaitonde: AstraZeneca: Current Employment, Current holder of stock options in a privately-held company, Research Funding. Emeribe: AstraZeneca: Current Employment, Current holder of stock options in a privately-held company. Cai: Celgene Corporation: Ended employment in the past 24 months; Google: Current equity holder in publicly-traded company; AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Mato: Johnson and Johnson: Consultancy, Research Funding; MSKCC: Current Employment; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Genmab: Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Nurix: Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; AstraZeneca: Consultancy.

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

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 517-517 ◽  
Author(s):  
Stephen G O'Brien ◽  
Corinne Hedgley ◽  
Sarah Adams ◽  
Letizia Foroni ◽  
Jane F. Apperley ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Blast Crisis ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
The Difference

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

Prognostic Factors for Developing Thrombosis in Polycytemia Vera: A Retrospective Analysis of 331 Patients with Long-Term Follow-up Highlights the Importance of White Blood Cells Levels

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 48-49
Author(s):  
Samantha Ferrari ◽  
Chiara Pagani ◽  
Mariella D'Adda ◽  
Nicola Bianchetti ◽  
Annamaria Pelizzari ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
High Risk ◽  
Board Of Directors ◽  
Advisory Board ◽  
Advisory Committees ◽  
Risk Status ◽  
History Of ◽  
Wbc Count

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis, constitutively active mutations in JAK2 and an increased susceptibility to thrombotic events (TEs). There is still controversy about the role of increased hematocrit and of other variables including elevated white blood cell count as risk factors for the occurrence of TEs. A better definition of the relative prognostic importance of hematologic parameters would help us to better tailor the therapeutic approach to PV patients (pts), which is currently mainly based on the use of acetilsalycilic acid (ASA), venesection and hydroxyurea . The aim of our study was to analyze if any clinical or laboratory variables were significantly associated to the occurrence of TEs both at PV diagnosis and during the course of the disease in a large series of PV pts uniformly followed at a single Center over a period of 29.5 years from January 1986 to June 2019. Clinical and laboratory data were obtained from the time of diagnosis until death, progression to acute leukemia or last follow-up. Hematocrit (Hct), hemoglobin (Hb), white blood cell (WBC) and platelet (PLT) levels were recorded for each patient at least every 6 months. Among a total of 331 pts, the median age was 65 years (range 30-92 years), and 56% were male. "High risk" features (age ≥ 60 years and/or history of prior thrombosis) were present in 221 pts (66.7%). The incidence of cardiovascular risk factors was: hypertension 64%, diabetes 15%, hyperlipidemia 28%, history of active or remote smoking 41%. Patients on ASA were 279 (84%), 19 (6%) were on oral anticoagulation, while 27 (8%) were on ASA+oral anticoagulant. At PV diagnosis 54 pts (16%) presented with thrombosis, arterial in 32 (59%) and venous in 22 (41%). A previous TE was recorded in 57 pts (17%): in 43 (75%) arterial, in 12 (22%) venous and in 2 (3%) mixed (arterial+venous). Previous thrombosis was the only variable significantly associated with the presence of a TE at PV diagnosis (P=0.02). After PV diagnosis, with a median follow-up of 81 months (range 1-374 months), 63 pts (19%) experienced a TE and 11 of them a further episode, for a total of 74 TEs. The incidence rate (pts/year) of TEs was 2.7%. Forty-two events were arterial (57%), 31 were venous (42%) and 1 (1%) was mixed. It was the first TE for 37 pts. Cerebrovascular accidents and deep-venous thrombosis were the most frequent arterial and venous TEs both at PV diagnosis and throughout the disease course, with a relative incidence of 50% and 32% respectively. The table compares the characteristics of patients who did or did not develop a TE after PV diagnosis. At univariate analysis, PV high risk status, a previous TE and hyperlipidemia at PV diagnosis were significantly associated with a subsequent TE. Among hematologic variables an elevated WBC count at the time of thrombosis, but not Hct or PLT levels, was highly significantly associated with the development of a TE. At multivariate analysis, WBC count ≥10.4 x 10^9/L and hyperlipidemia maintained their independent prognostic value, while high risk status and a previous TE lost their prognostic significance. Both at univariate and multivariate analysis, hyperlipidemia at diagnosis (P=0.009 and P=0.002) and high WBC count at thrombosis (P=0.001 and P=&lt;0.0001) predicted for arterial thromboses, while only a history of prior thrombosis (P=0.03) predicted for venous ones. In conclusion, our analysis confirms that elevated WBC count at the moment of the event more than increased hematocrit is associated to the development of thrombosis in PV pts. We also found that hyperlipidemia was an independent risk factor for arterial thrombosis, calling for an accurate management of increased lipid levels. Whether a reduction of the WBC count during the course of PV may reduce the frequency of TE remains to be demonstrated by prospective studies. Table Disclosures D'Adda: Novartis: Other: Advisory board; Incyte: Other: Advisory board; Pfizer: Other: Advisory board. Rossi:Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4619-4619
Author(s):  
Jee Yon Shin ◽  
Sung-Soo Park ◽  
Gi June Min ◽  
Silvia Park ◽  
Sung-Eun Lee ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Advisory Committees ◽  
Sibling Donor ◽  
Alternative Donor ◽  
Matched Sibling ◽  
Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document