scholarly journals High-risk additional chromosomal abnormalities at low blast counts herald death by CML

Leukemia ◽  
2020 ◽  
Vol 34 (8) ◽  
pp. 2074-2086 ◽  
Author(s):  
Rüdiger Hehlmann ◽  
◽  
Astghik Voskanyan ◽  
Michael Lauseker ◽  
Markus Pfirrmann ◽  
...  
Keyword(s):  
High Risk ◽  
Chromosomal Abnormalities ◽  
Cox Model ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Response To Therapy ◽  
Low Risk ◽  
Diagnostic Systems ◽  
Impact On Survival ◽  
Additional Chromosomal Abnormalities

Abstract Blast crisis is one of the remaining challenges in chronic myeloid leukemia (CML). Whether additional chromosomal abnormalities (ACAs) enable an earlier recognition of imminent blastic proliferation and a timelier change of treatment is unknown. One thousand five hundred and ten imatinib-treated patients with Philadelphia-chromosome-positive (Ph+) CML randomized in CML-study IV were analyzed for ACA/Ph+ and blast increase. By impact on survival, ACAs were grouped into high risk (+8, +Ph, i(17q), +17, +19, +21, 3q26.2, 11q23, −7/7q abnormalities; complex) and low risk (all other). The presence of high- and low-risk ACAs was linked to six cohorts with different blast levels (1%, 5%, 10%, 15%, 20%, and 30%) in a Cox model. One hundred and twenty-three patients displayed ACA/Ph+ (8.1%), 91 were high risk. At low blast levels (1–15%), high-risk ACA showed an increased hazard to die compared to no ACA (ratios: 3.65 in blood; 6.12 in marrow) in contrast to low-risk ACA. No effect was observed at blast levels of 20–30%. Sixty-three patients with high-risk ACA (69%) died (n = 37) or were alive after progression or progression-related transplantation (n = 26). High-risk ACA at low blast counts identify end-phase CML earlier than current diagnostic systems. Mortality was lower with earlier treatment. Cytogenetic monitoring is indicated when signs of progression surface or response to therapy is unsatisfactory.

scholarly journals High-Risk Additional Chromosomal Abnormalities in CML Herald Death By Blast Crisis Already at Low Blast Levels

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 666-666 ◽  
Author(s):  
Rüdiger Hehlmann ◽  
Astghik Voskanyan ◽  
Michael Lauseker ◽  
Markus Pfirrmann ◽  
Lida Kalmanti ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Blast Crisis ◽  
Intensive Therapy ◽  
Chronic Phase ◽  
Response To Therapy ◽  
Low Risk ◽  
University Hospital ◽  
Additional Chromosomal Abnormalities

Background. The end phase or metamorphosis is one of the remaining challenges of chronic myeloid leukemia (CML) management. Blast crisis (BC) is a late marker. Earlier diagnosis may improve outcome. The detection of additional chromosomal abnormalities (ACA) at low blast levels might allow earlier treatment when outcome is better. Methods. We made use of 1536 Ph+CML-patients in chronic phase followed in the randomized CML study IV (Hehlmann et al, Leukemia 2017) for a median of 8.6 years. 1510 cytogenetically evaluable patients were analyzed for ACA and blast increase (Flow chart). According to impact on survival ACA were grouped into high-risk (+ 8; +Ph; i(17q); +17; +19 +21; 3q26; 11q23; -7; complex) and low-risk (all other). Prognosis with +8 alone was clearly better than with +8 accompanied by further abnormalities, but still worse than with low-risk ACA. +8 alone was therefore included in the high-risk group. The presence of high- and low-risk ACA was linked to 6 thresholds of blast increase (1%, 5%, 10%, 15%, 20%, and 30%) in a Cox proportional hazards model. Results. 139 patients (9.2%) displayed ACA at any time before BC diagnosis, 88 (5.8%) had high-risk and 51 (3.4%) low-risk ACA. ACA emerged after a median of 17 (0-133) months. 79 patients developed BC. 43 (61%) of 71 cytogenetically evaluable patients with BC had high-risk ACA. 3-year survival after emergence of high-risk ACA was 48%, after emergence of low-risk ACA 92%. At low blast levels (1-15%), high-risk ACA showed an increased hazard to die (ratios: 3.66 in blood; 6.84 in marrow) compared to no ACA in contrast to low-risk ACA. This effect was not observed anymore at blast increases to 20-30% (Figure). 38 patients with high-risk ACA died, 36 with known causes of death which were almost exclusively BC (n=26, 72%) and progression-related transplantation (n=8, 22%). Only 2 patients died of CML-unrelated causes. Conclusions. High-risk ACA herald death by BC already at low blast levels and may help to define CML end phase in a subgroup of patients at an earlier time than is possible with current blast thresholds. Cytogenetic monitoring is indicated when signs of progression surface and response to therapy is unsatisfactory. More intensive therapy may be indicated at emergence of high-risk ACA. Disclosures Hehlmann: Novartis: Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Fabarius:Novartis: Research Funding. Krause:Siemens: Research Funding; Takeda: Honoraria; MSD: Honoraria; Gilead: Other: travel; Celgene Corporation: Other: Travel. Baerlocher:Novartis: Research Funding. Burchert:Novartis: Research Funding. Brümmendorf:Novartis: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Ariad: Consultancy; Pfizer: Consultancy, Research Funding; University Hospital of the RWTH Aachen: Employment. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Saussele:BMS: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria, Research Funding. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy.

scholarly journals Polygenic risk scores predict diabetic complications and their response to therapy

2019 ◽  
Author(s):  
J. Tremblay ◽  
M. Haloui ◽  
F. Harvey ◽  
R. Tahir ◽  
F.-C. Marois-Blanchet ◽  
...  
Keyword(s):  
High Risk ◽  
Prediction Model ◽  
Risk Group ◽  
Intensive Therapy ◽  
Cardiovascular Death ◽  
Response To Therapy ◽  
Low Risk ◽  
Number Needed To Treat ◽  
Genome Wide Association Studies ◽  
Increased Risk

AbstractType 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction can lead to timely intervention and better outcomes. Through summary statistics of meta-analyses of published genome-wide association studies performed in over 1.2 million of individuals, we combined 9 PRS gathering genomic variants associated to cardiovascular and renal diseases and their key risk factors into one logistic regression model, to predict micro- and macrovascular endpoints of diabetes. Its clinical utility in predicting complications of diabetes was tested in 4098 participants with diabetes of the ADVANCE trial followed during a period of 10 years and replicated it in three independent non-trial cohorts. The prediction model adjusted for ethnicity, sex, age at onset and diabetes duration, identified the top 30% of ADVANCE participants at 3.1-fold increased risk of major micro- and macrovascular events (p=6.3×10−21 and p=9.6×10−31, respectively) and at 4.4-fold (p=6.8×10−33) increased risk of cardiovascular death compared to the remainder of T2D subjects. While in ADVANCE overall, combined intensive therapy of blood pressure and glycaemia decreased cardiovascular mortality by 24%, the prediction model identified a high-risk group in whom this therapy decreased mortality by 47%, and a low risk group in whom the therapy had no discernable effect. Patients with high PRS had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years. This novel polygenic prediction model identified people with diabetes at low and high risk of complications and improved targeting those at greater benefit from intensive therapy while avoiding unnecessary intensification in low-risk subjects.

scholarly journals MO048MULTICENTRE PROSPECTIVE VALIDATION OF THE URINARY PEPTIDOME-BASED CLASSIFIER CKD273 AS A PREDICTOR OF RENAL FUNCTION DECLINE IN SUBJECTS WITH TYPE 2 DIABETES

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Morten Lindhardt ◽  
Nete Tofte ◽  
Gemma Currie ◽  
Marie Frimodt-Moeller ◽  
Heiko Von der Leyen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Renal Function ◽  
High Risk ◽  
Risk Group ◽  
Cox Model ◽  
Risk Groups ◽  
High Risk Group ◽  
Low Risk ◽  
Renal Function Decline

Abstract Background and Aims In the PRIORITY study, it was recently demonstrated that the urinary peptidome-based classifier CKD273 was associated with increased risk for progression to microalbuminuria. As a prespecified secondary outcome, we aim to evaluate the classifier CKD273 as a determinant of relative reductions in eGFR (CKD-EPI) of 30% and 40% from baseline, at one timepoint without requirements of confirmation. Method The ‘Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria trial’ (PRIORITY) is the first prospective observational study to evaluate the early detection of diabetic kidney disease in subjects with type 2 diabetes (T2D) and normoalbuminuria using the CKD273 classifier. Setting 1775 subjects from 15 European sites with a mean follow-up time of 2.6 years (minimum of 7 days and a maximum of 4.3 years). Patients Subjects with T2D, normoalbuminuria and estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73m2. Participants were stratified into high- or low-risk groups based on their CKD273 score in a urine sample at screening (high-risk defined as score > 0.154). Results In total, 12 % (n = 216) of the subjects had a high-risk proteomic pattern. Mean (SD) baseline eGFR was 88 (15) ml/min/1.73m2 in the low-risk group and 81 (17) ml/min/1.73m2 in the high-risk group (p < 0.01). Baseline median (interquartile range) urinary albumin to creatinine ratio (UACR) was 5 (3-8) mg/g and 7 (4-12) mg/g in the low-risk and high-risk groups, respectively (p < 0.01). A 30 % reduction in eGFR from baseline was seen in 42 (19.4 %) subjects in the high-risk group as compared to 62 (3.9 %) in the low-risk group (p < 0.0001). In an unadjusted Cox-model the hazard ratio (HR) for the high-risk group was 5.7, 95 % confidence interval (CI) (3.9 to 8.5; p<0.0001). After adjustment for baseline eGFR and UACR, the HR was 5.2, 95 % CI (3.4 to 7.8; p<0.0001). A 40 % reduction in eGFR was seen in 15 (6.9 %) subjects in the high-risk group whereas 22 (1.4 %) in the low-risk group developed this endpoint (p<0.0001). In an unadjusted Cox-model the HR for the high-risk group was 5.0, 95 % CI (2.6 to 9.6; p<0.0001). After adjustment for baseline eGFR and UACR, the HR was 4.8, 95 % CI (2.4 to 9.7; p<0.0001). Conclusion In normoalbuminuric subjects with T2D, the urinary proteomic classifier CKD273 predicts renal function decline of 30 % and 40 %, independent of baseline eGFR and albuminuria.

Response to Therapy with Imatinib Mesylate in Patients with CML Is Poor in Non-Caucasian Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2937-2937
Author(s):  
Sarah George ◽  
Laura Horvath ◽  
Robert Molokie ◽  
John Berry ◽  
Damiano Rondelli ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Response Rates ◽  
Complete Response ◽  
Response To Therapy ◽  
Low Risk ◽  
Risk Scores ◽  
Genetic Characteristics

Abstract Imatinib mesylate is a targeted therapy for chronic myeloid leukemia (CML). All phases of CML are susceptible to imatinib, with more durable responses occurring in patients in chronic phase. Studies in patients with chronic phase CML who have been treated with imatinib have shown a complete hematologic remission (CHR) rate of 97%, a complete cytogenetic remission (CCR) rate of 70%, and a complete molecular remission (CMR) rate of 10%. Racial and ethnic differences have not been extensively studied in relation to cancer outcomes, and no studies to date have demonstrated a difference in outcomes based upon race or ethnicity of patients with CML treated with imatinib. Methods : A retrospective chart review of patients with CML who have been treated with imatinib at the University of Illinois, the Westside VA, and MacNeal hospitals over the past 3 years was performed. Primary endpoints were rates of CHR, CCR, and CMR in Caucasian (C) and non-Caucasian (NC) patients with CML on treatment with imatinib. A secondary endpoint was the correlation of Sokal scores at initiation of imatinib with rates of CHR, CCR, and CMR. Results: 26 charts were reviewed of 7 C and 19 NC patients ( 12 African American, 5 Latino, 1 Indian, 1 Lebanese) in chronic phase CML. For C patients at the initiation of imatinib, mean age was 46 (45 for NC) and mean Sokal score was 0.79 (0.75 for NC). 32% (8/25) of patients had cytogenetic abnormalities in addition to the Philadelphia chromosome, all of whom were NC (50% were pretreated; 29% obtained CCR). Mean duration from diagnosis to treatment with imatinib was 5 months for C and 9 months for NC. Mean length of follow up while on imatinib was 28 months for C and 14 months for NC, with early termination due to lack of follow up, progression of disease, and death. 31% (8/26) of patients (25% C, 75% NC) had received prior treatments with agents such as IFN, AraC, busulfan, anagrelide, homoharrington, and allogeneic SCT. 100% of pretreated C had CCR (vs 33% of pretreated NC). CHR rate was 100% in C (4/4) vs. 87.5% (14/16) in NC. CCR was obtained in 100% of C (6/6) but only 14% (2/14) of NC. CMR rate was noted to be 33% (1/3) in Caucasians compared to 8.3% (1/12) in NC. Low risk Sokal scores were associated with CHR rate of 100% in C (3/3) and 75% (6/8) in NC, as well as CCR rate of 100% in C (5/5) and only 25% (2/8) in NC. Conclusions: NC patients have a poorer response to treatment with imatinib for CML. The discrepancy between complete response rates (most notably the CCR rate) between C and NC patients could be accounted for by differences in the genetic characteristics of the disease, metabolism, or adherence rates. NC patients with low risk Sokal scores also had poorer complete response rates than C patients with the same risk scores. Prospective studies are needed to further evaluate these differences and discern their etiology. Given poor CCR rates, NC patients should be HLA typed soon after diagnosis and considered for transplant if a matched donor is available.

Evaluation of the Clinical Significance of Immunophenotyping in Myelodysplastic Syndrome.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4834-4834
Author(s):  
Dan D. Liu ◽  
Xue L. Jiao ◽  
Mei J. Geng ◽  
Ming Q. Zhu ◽  
Jing X. Gong ◽  
...  
Keyword(s):  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Chromosomal Abnormalities ◽  
Bone Marrow Cells ◽  
Cell Lineage ◽  
Low Risk ◽  
Specific Marker ◽  
Myeloid Lineage ◽  
Hematologic Disorder ◽  
Myeloid Antigens

Abstract The myelodysplastic syndrome (MDS) is a clonal hematologic disorder with extremely heterogeneous cell component. Diagnosis is currently depending on the dysplastic morphology of bone marrow cells and the presence of specific cytogenetic abnormalities. Since no specific marker could be identified in MDS, it is sometimes hard to distinguish from other anemias, such as aplastic anemia (AA). The cell immunotype may be helpful in differential diagnosis and predicting the disease progress. To evaluate the clinical usage of immunotyping in MDS patients, we have compared the immunotypes between 36 MDS patients, 18 patients with AA and 11 healthy controls by using flow cytometry. Moreover, in combination with karyotype analysis and prognosis indicator IPSS, the value of immunotyping was further analyzed and discussed. Our results demonstrated: In MDS-RA patients, the distribution of surface antigen on BM cells had no preferential difference between lymphoid and myeloid lineages. In RAEB patients, expressions of CD13, CD33 and CD34 were prevailing, significantly higher than others(P<0.05). In contrast, in AA patients, expressions of CD2, CD7, CD19, CD20 were significantly higher than other surface antigens(P<0.05). In high risk MDS (RAEB/RAEB-t) patients, the cells expressing B cell lineage antigens (CD19,CD20) are markedly less than that in healthy people(P<0.05)while percentage of myeloid lineage antigen (CD13,CD33) are much higher than that in health control(P<0.05), However, in low risk MDS patients (RA) the frequency of expression of all myeloid, T and B lymphoid lineage antigens were not different from that in health controls. The distribution pattern of these three lineage antigens in high risk MDS patients was remarkably different with those of AA patients(P<0.05). Comparing with low-risk MDS, high-risk MDS expressed more myeloid lineage antigens (P<0.05)while expressed less B lineage antigens(P<0.05). In MDS patients, expression of CD14 was correlated with special chromosomal abnormalities defined by IPSS Our results suggested: The pattern of immunotype distribution in MDS cells are highly heterogenous. Expressions of myeloid antigens was predominant in MDS patients. Immunotyping can be helpful for discriminating MDS from AA and for monitoring the disease progression from low risk to high risk MDS. Expressions of certain immunotype are correlated with prognosis of MDS.

Additional Chromosomal Abnormalities in Philadelphia Chromosome-Negative Metaphases Appearing during Therapy with Imatinib, Dasatinib, Nilotinib and Ponatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1577-1577 ◽  
Author(s):  
Ghayas C. Issa ◽  
Hagop M. Kantarjian ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Clinical Outcomes ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Banding Technique ◽  
First Year ◽  
Additional Chromosomal Abnormalities

Abstract Background Additional chromosomal abnormalities (ACAs) in the Philadelphia chromosome (Ph)-negative metaphases that emerge as patients with chronic myeloid leukemia (CML) are treated with tyrosine kinase inhibitors (TKIs) have been reported during treatment with imatinib. It has been suggested that these might be associated with an inferior outcome and in rare instances lead to the emergence of a new malignant clone resulting in myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (Jabbour et. al, Blood 2007). This phenomenon has not been well characterized when other TKIs are used. We conducted a retrospective analysis of patients treated on imatinib, dasatinib, nilotinib, and ponatinib frontline trials to assess the frequency and prognostic impact of ACAs appearing during the treatment after achieving cytogenetic response. Patients and Methods A total of 524 patients with CML were evaluated with a median age at diagnosis of 48 years (range 15 to 86). These included 236 patients treated with imatinib, 125 with nilotinib, 118 with dasatinib and 45 with ponatinib. All the patients were treated in clinical trials approved by the institutional board review and signed an informed consent in accordance with institutional guidelines and in accordance with the declaration of Helsenki. Conventional cytogenetic analysis was done in bone marrow cells using standard G-banding technique at baseline, every 3 months during the first year, then every 6-12 months. Clonal ACAs were identified as abnormalities present in ≥2/20 metaphases or, if only one metaphase, present in ≥2 consecutive assessments. Results After a median follow-up of 83.8 months (range 0.3-176.6 months) 13% (72/524) patients had ACAs, of which 7% (41/524) were clonal. ACAs were seen in 11% (27/236) of patients on imatinib compared to 11% (13/118, p=0.9) on dasatinib, 19 % (24/125, p= 0.04) on nilotinib, and 17% (8/45, p=0.2) on ponatinib. Six patients had both clonal evolution (CE) and ACAs at different times. The median number of metaphases containing ACAs was 5/20 (range 1 to 20) with an average of 7/20. Most appeared within the first year of the start of the TKI (median 6 months, range 3-72 months); they first appeared after 12 months of therapy in 21 of the 72 (29%) patients. ACAs were transient and were detected in 2 or less time points in 52 of the 72 (72%) cases. The most common clonal ACAs were - Y (13/41) and +8 (4/41). The rates of cytogenetic and molecular responses were similar for patients with and without clonal ACAs (CCyR: 88% vs 91%; p=0.55) (MMR: 78% vs 86%, p=0.20). Having clonal ACAs did not affect the rate of deep molecular response either (MR4.5 71% vs 67%; p =0.65). There was no significant difference in EFS and OS (5y EFS 73% vs 86%; p=0.19) (5y OS 77% vs 93%; p=0.06) although there was a trend for lower rates for both. Responses and clinical outcomes were similar between different TKIs for patients with and without clonal ACAs. One patient with -7 treated with ponatinib developed MDS. Monosomy 7 appeared 9 months from the start of treatment in 9/20 metaphases and persisted. He was taken off ponatinib because of pancytopenia. He subsequently received bosutinib, achieved and maintained a CCyR. A high-risk MDS was documented approximately 1 year after appearance of the -7 clone. He was started on decitabine and achieved a partial cytogenetic response for MDS. Another patient in the imatinib cohort with -7 developed secondary AML (CCyR for CML) and died from a multiple organ failure after allogeneic stem cell transplant from a one antigen-mismatched unrelated donor. There was a third patient with -7 that later had CE and developed Ph+ CML blast phase. Conclusion ACAs are rare and mostly transient events that appear during the treatment of CML with TKIs. These changes do not affect responses or clinical outcomes, independent of what TKI is used. A small subset of patients with -7 may develop AML or MDS warranting close monitoring of patients with changes that are reminiscent of those diseases. Molecular analysis after appearance of ACAs could help identify mutations driving the Ph-clone into AML or MDS. Disclosures Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:BerGenBio AS: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

scholarly journals Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: To Allogeneic Stem Cell Transplantation or Not? a Single Center Experience

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2308-2308 ◽  
Author(s):  
xiao-Jun Huang ◽  
Jing Wang ◽  
Qian Jiang ◽  
Huan Chen ◽  
Lanping Xu ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Low Risk ◽  
Consolidation Chemotherapy ◽  
High Level

Abstract Objectives: Compare the outcomes of allogeneic stem cell transplantation (allo-HSCT) versus a combination of imatinib and chemotherapy in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Explore prognostic factors and indentify those who may enjoy long-term survival without the risk of allo-HSCT. Methods: Between May 2006 to November 2015, data of consecutive newly-diagnosed Ph+ALL patients <65 years treated at Peking University People's Hospital were analyzed retrospectively. Patients received imatinib 400mg daily plus CODP regimen as induction chemotherapy. After achieving a complete remission (CR), they received imatinib with 8 cycles of alternating reduced-intensity hyper-CVAD regimen as consolidation chemotherapy. Patients in CR continued maintenance imatinib, vincristine, and prednisone for 2 years, which was followed by imatinib indefinitely. Patients eligible for allo-HSCT underwent it based on their own choice after at least 2 cycles of consolidation regimen during their first CR. Minimal residual disease (MRD) for BCR-ABL by quantitative polymerase chain reaction was monitored after each cycle of induction and consolidation chemotherapy and every 3 months later. Dasatinib was used as the second-line tyrosine kinase inhibitors (TKI) once imatinib-resistance occurred. Results: 122 Ph+ALL patients were included. 64 patients were male (52.5%). Median age was 36 years (range, 14-65 years). 2 patients (1.6%) died before response assessment, and 115 (95.8%) achieved CR. With a median followed-up period of 20 months (range, 1-98 months) in all patients and 28 months (range, 4-98 months) in 99 survivors, 65 patients (56.5%) underwent allo-HSCT and 50 (43.5%) received continuous imatinib with chemotherapy. Cumulative incidence of relapse (CIR), disease-free survival (DFS) and overall survival (OS) rates at 3 years were 17.3%, 79.0% and 81.5%, respectively. Multivariate analyses in the total CR patients showed that BCR-ABL reduction <3 logs from baseline after 2 cycles of consolidation chemotherapy (defined as MRD high level; HR=7.7, 95%CI 2.0-25.0, P=0.002; HR=2.9, 95%CI 1.1-7.1, P=0.026; HR=7.6, 95%CI 1.6-13.7, P=0.009) and imatinib plus chemotherapy (HR=7.1, 95%CI 2.6-20.0, P<0.001; HR=6.1, 95%CI 2.4-15.8, P<0.001; HR=5.6, 95%CI 2.0-15.8, P=0.001) were factors associated with increasing CIR and shorter DFS and OS. In addition, WBC equal or more than 30 X 109/L at diagnosis (HR=2.3, 95%CI 1.1-6.2, P=0.032; HR=4.1, 95%CI 1.3-13.2, P=0.016) was associated with shorter DFS and OS. In an attempt to determine whether choice of therapy contributed to outcome differences among patients with or without common poor prognostic factors (WBC equal or more than 30 X 109/L at diagnosis and MRD high level) for DFS and OS, we categorized the entire cohort into low-risk (possessing none of the factors, n=33), intermediate-risk (possessing any one of the factors, n=45), or high-risk (possessing at least 2 factors, n=24). In the low-risk cohort, choice of therapy did not influence the outcomes. In the intermediate- and high- risk cohorts, treatment with allo-HSCT was significantly superior to imatinib plus chemotherapy, with 3-year CIR, DFS and OS rates of 3.4% versus 44.3% (P=0.001) and 6.2% versus 55.6% (P=0.009); 88.2% versus 51.3% (P=0.001) and 93.8% versus 37.5% (P=0.027); 91.7% versus 56.3% (P=0.001) and 93.8% versus 41.0% (P=0.021), respectively. (Figure) Conclusions Our data suggest that allo-HSCT is a viable option for all patients with Ph+ALL. It is superior to a combination of imatinib and chemotherapy, conferring significant survival advantages to intermediate- and high-risk patients. However, the outcomes of imatinib plus chemotherapy and allo-HSCT are equally good in low-risk patients. For such patients, allo-HSCT may be considered as a salvage potion if there is evidence of TKI(s) resistance so long as the MRD is carefully monitored. Outcomes between allogeneic stem cell transplantation versus a combination of imatinib and chemotherapy. Outcomes between allogeneic stem cell transplantation versus a combination of imatinib and chemotherapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Correction: High-risk additional chromosomal abnormalities at low blast counts herald death by CML

Leukemia ◽  
2020 ◽  
Vol 34 (10) ◽  
pp. 2823-2823
Author(s):  
Rüdiger Hehlmann ◽  
◽  
Astghik Voskanyan ◽  
Michael Lauseker ◽  
Markus Pfirrmann ◽  
...  
Keyword(s):  
High Risk ◽  
Chromosomal Abnormalities ◽  
Additional Chromosomal Abnormalities

P1006IMPACT OF GLUCOSE-LOWERING AND ANTIHYPERTENSIVE MEDICATIONS ON DEVELOPMENT OF MICROALBUMINURIA IN SUBJECTS WITH TYPE 2 DIATETES AND NORMOALBUMINURIA IN THE PRIORITY STUDY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Nete Tofte ◽  
Morten Lindhardt ◽  
Gemma Currie ◽  
Marie Frimodt-Moeller ◽  
Heiko Von der Leyen ◽  
...  
Keyword(s):  
High Risk ◽  
Cox Model ◽  
Controlled Trial ◽  
Low Risk ◽  
Channel Blockers ◽  
Antihypertensive Medications ◽  
Converting Enzyme Inhibitors ◽  
Glucose Lowering ◽  
Increased Risk ◽  
Dipeptidyl Peptidase 4 Inhibitors

Abstract Background and Aims In the PRIORITY study, it was recently demonstrated that the urinary peptidome-based classifier CKD273 was associated with increased risk for progression to microalbuminuria. In this sub-study, we aim to evaluate whether glucose-lowering and antihypertensive medications, many of which have been demonstrated to have albuminuria-lowering effects, may interfere with the predictive value of CKD273. Method A post hoc analysis of a prospective observational study with embedded randomised placebo-controlled trial. Setting 1775 subjects from 15 European sites with a mean follow-up time of 2.6 years (minimum of 7 days and a maximum of 4.3 years). Patients Subjects with T2D, normoalbuminuria and estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73m2. Participants were stratified into high- or low-risk groups based on their CKD273 score in a urine sample at screening (high-risk defined as score &gt; 0.154). Main outcome measures Baseline medication or initiation during the study was assessed for the following medications: glitazones, glucagon-like peptide-1 receptor agonists (GLP1-RA), sodium-glucose cotransporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i), angiotensin-converting-enzyme inhibitors (ACEi), angiotensin-II-receptor blockers (ARB), calcium channel blockers (CCB) and beta blockers (BB). The main outcome was development of confirmed microalbuminuria (urinary albumin to creatinine ratio (UACR) &gt;30 mg/g and with ≥30% increase from baseline) in 2 of 3 consecutive samples. Results The hazard ratio (HR (95% CI)) for development of microalbuminuria (high vs. low-risk) was 3.9 (2.9-5.3) in a crude Cox-model; and 2.4 (1.8-3.4; p&lt;0.0001) when adjusted for age, sex, HbA1c, systolic blood pressure, retinopathy, eGFR and UACR. Adding baseline medications to the model did not significantly alter the results. When evaluating medications initiated during the study, more high- than low-risk subjects were started on glitazones, GLP1-RA, SGLT2i, CCB and BB (p&lt;0.03), however, only initiation of DPP4i was associated with the outcome. Adjustment for DPP4i initiated during the study did not significantly change the HR for development of confirmed microalbuminuria (HR 2.5 (1.8 to 3.4); p&lt;0.0001) in a model including eGFR and UACR. The HR for development of persistent microalbuminuria (spironolactone vs. placebo) was 0.81 (0.49-1.34; p=0.41), however, adjusting for DPP4i did not significantly alter this result. Conclusion Although several glucose-lowering and antihypertensive medications were more frequently prescribed in high-risk subjects, the CKD273 classifier prospectively predicted confirmed microalbuminuria, independent of baseline co-medications and medication initiated during the study. Moreover, initiated medications during the study could not explain the inability of spironolactone to delay progression to microalbuminuria.

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