Therapy With Demethylating Agents Significantly Improves Overall- and AML-Free Survival In Patients With MDS Classified As High-Risk By IPSS Or Very High Risk By IPSS-R and Partial Or Total Monosomy 7-Results From a German Multicenter Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2784-2784 ◽  
Author(s):  
Julie Schanz ◽  
Friederike Braulke ◽  
Katayoon Shirneshan ◽  
Kathrin Nachtkamp ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
High Risk ◽  
Supportive Care ◽  
Median Time ◽  
Research Funding ◽  
Risk Group ◽  
Best Supportive Care ◽  
High Risk Group ◽  
Monosomy 7 ◽  
Free Survival ◽  
Very High

Abstract Introduction Total (-7) or partial (7q-) monosomy 7 is frequent in malignant myeloid disorders, observed in around 12% of MDS/AML and up to 40% of therapy-associated MDS/AML. Monosomy 7 is associated with poor outcome, high susceptibility to infections and poor response to chemotherapy. A therapeutic benefit for 5-azacytidine was previously described (Fenaux et al., 2009). The present study was designed to analyze clinical features, prognosis and response to different therapeutic strategies in patients with monosomy 7 in a multicentric, retrospective German cohort study. Patients and methods Currently, 231 patients with MDS/AML following MDS and monosomy 7 were included. Inclusion criteria were defined as follows: Morphologic diagnosis of MDS/AML following MDS, age ≥18 years, bone marrow blast count ≤30% and presence of -7 or 7q-. The data was assembled from centers in Düsseldorf, (n=120; 52%), Cologne (n=38; 17%), Freiburg (n=31; 13%), Göttingen (n=14; 6%), Munich (n=13; 6%), Dresden (n=11; 5%) and Mannheim (n=4; 2%). The median age in the study cohort was 67 years, 65% of patients were males. 29/231 patients (13%) were diagnosed as AML following MDS. MDS/AML was therapy-associated in 24 patients (11%). Regarding IPSS, 38 (19%) were classified as low/intermediate 1 risk and 165 (81%) as intermediate-2/high-risk. According to IPSS-R, 2 (1%) were assigned to the very-low/low risk group, 31 (16%) to the intermediate group, 52 (27%) to the high-risk group and 107 (56%) to the very high risk group. The treatment was classified as follows: Best supportive care (BSC), low-dose Chemotherapy (LDC), high-dose chemotherapy (HDC), demethylating agents (DMA; either 5-azacytidine or decitabine), and others. Results A best supportive care regimen was chosen in nearly half of the patients (49%). The remaining patients received 1-4 sequential therapies (1: 29%; 2: 11%; 3: 10%; 4: 1%). As the first line therapy, 64 patients (54%) received DMA, 24 (20%) an allo-Tx, 9 (8%) HDC, 5 (4%) LDC, and 16 (14%) were treated with other therapies. The best prognosis was observed in patients eligible for allo-Tx: The median OS in transplanted patients was 924 days as compared to 361 days (p<0.01) in patients not eligible for transplantation. In the latter cohort, patients who received DMA at any course of their disease did not differ from those receiving other therapies: The median OS was 468 days in patients treated with DMA as compared to 325 on those with alternative therapies (p not significant) and the median time to AML-transformation was 580 versus 818 days (p not significant), respectively. However, by classifying patients according to IPSS- and IPSS-R, it became obvious that patients with an IPSS high-risk or an IPSS-R very high risk showed a clear benefit from DMA: In the first group, median OS was 444 days in DMA-treated and 201 days in non-DMA-treated patients (p=0.048), in the latter group, median OS 444 days in the DMA-treated and 203 days in the non-DMA treated cohort (p=0.017). Comparable results were observed regarding AML-free survival: Median time to AML was 580 (DMA) vs. 186 (no DMA) days in IPSS high risk patients (p=0.031) and 580 (DMA) vs. 273 (no DMA) days in the IPSS-R very high risk group (p not significant). Conclusions Patients with MDS, partial or total monosomy 7 and a high risk according to IPSS or a very high risk according to IPSS-R show a pronounced benefit when treated with DMA, regarding overall- as well as AML-free survival. Further results from the ongoing data analysis will be presented in detail. The study was supported by research funding from Celgene. Disclosures: Schanz: Celgene: Research Funding. Braulke:Celgene: Research Funding. Germing:Celgene: Honoraria, Research Funding. Schmitz:Novartis: Research Funding; Celegene: Consultancy, Research Funding, Speakers Bureau. Götze:Celgene: Honoraria. Platzbecker:Celgene: Honoraria, Research Funding. Haase:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

scholarly journals Clinical Characteristics and Treatment Allocations in Patients with Myelodysplastic Syndromes and Monosomy 7: Results from an International Multicenter Study Suggest That Hypomethylating Agents Significantly Improve Overall- and AML-Free Survival in Patients Classified As Very High Risk By IPSS-R

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4656-4656 ◽  
Author(s):  
Julie Schanz ◽  
Friederike Braulke ◽  
Ghulam J. Mufti ◽  
Elena Crisà ◽  
Austin Kulasekararaj ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Research Funding ◽  
Risk Group ◽  
Best Supportive Care ◽  
High Risk Group ◽  
Study Cohort ◽  
Monosomy 7 ◽  
Free Survival ◽  
Very High

Abstract Introduction: Total (-7) or partial (7q-) monosomy 7 is the second frequent abnormality in MDS, occurring in around 12% of MDS/AML and up to 40% of therapy-associated MDS/AML. The present study was designed to analyze clinical features, prognosis and response to different therapeutic strategies in patients with -7 or del(7q) in a multicentric, retrospective cohort study. Patients and Methods: 471 patients with MDS/AML following MDS and monosomy 7 were registered and retrospectively analyzed. The median observation time was 3.6 years. Inclusion criteria were defined as follows: Morphologic diagnosis of MDS/AML following MDS, bone marrow blast count <=30% and presence of -7 or 7q- proved by chromosome banding analysis (CBA) or fluorescence in situ-hybridization (FISH). The data was coalesced from 8 centers in London (n=140; 29.7%), Duesseldorf, (n=120; 25.5%%), Goettingen (n=118; 25.1%), Cologne (n=38; 8.1%), Freiburg (n=29; 6.2%), Munich (n=13; 2.8%), Dresden (n=10; 2.1%) and Mannheim (n=3; 0.6%). The median age in the study cohort was 66 years, 63% of patients were males. MDS/AML was therapy-associated in 53 (11%). According to IPSS-R, 9 (1.9%) were assigned to the low risk group, 39 (8.3%) to the intermediate group, 81 (17.2%) to the high-risk group and 133 (28.2%) to the very high risk group. The treatment was classified as follows: Best supportive care (BSC), low-dose Chemotherapy (LDC), high-dose chemotherapy (HDC), hypomethylating agents (HMA; either 5-azacytidine or decitabine), and others (e.g. valproic acid, steroids, lenalidomide or thalidomide). Survival analyses were performed regarding overall- (OS) as well as AML-free survival (AFS) using the Kaplan-Meier method. Results: 147 patients (31.2%) showed 7q-, 313 (66.5%) -7 and 11 (2.3) patients showed both abnormalities at the first cytogenetic examination. The abnormality was detected by CBA±FISH in 440 (93.4%) and by FISH only in 31 (6.6%). In the latter cases, the CBA was either unsuccessful or showed a normal karyotype. In 182 (38.6%) patients, -7/del7q was detected as a single abnormality, 77 (16.3%) showed two abnormalities and 184 (39.1%) showed a complex karyotype involving -7/7q-. As previously described (Schanz et al., 2012), untreated patients with an isolated 7q- as compared to an isolated -7 show a better prognosis regarding OS (median: 4.0 vs. 0.7 years; p<0.01) as well as AFS (median not reached vs. 2.3 years; p=0.062). Median hemoglobin level in the study cohort was 9.3 g/dl, ANC 0.98*103/μl, platelet count 73*103/μl and the median number of bone marrow blasts was 8%. Regarding the treatment, a best supportive care regimen was chosen in 195 (41%) patients. The remaining 276 (58.6) patients received 1-5 sequential therapies (one therapy: 31.6%; more than 1 therapy: 27.0%). 81 patients received an allogeneic bone marrow transplantation (ATX). Within the group of patients treated with HMA at any time of their disease (n=167), 147 (31.2%) received 5-Azacytidine, 8 (1.7%) Decitabine and 12 (2.5%) patients were treated with both drugs. As the first line therapy, 122 patients (25.9%) received HMA, 50 (10.6%) HDC, 28 (5.9%) ATX, 28 (5.9%) 11 (2.3%) LDC, and 28 (5.9%) were treated with other therapies. Patients eligible for ATX showed a significantly better prognosis as compared to any other therapy strategy: The median OS in was 2.1 years as compared to 1.1 years in non-transplanted patients (p<0.01). In patients not eligible for ATX, treatment with HMA at any course of their disease as compared to a BSC strategy was associated with a better OS (1.4 vs. 0.8 years, p=0.014). By comparing HMA to any other therapy, the OS did not differ significantly (1.4 years in HMA vs. 1.1 years in any other, p n.s.). In patients classified as very high risk according to IPSS-R, the median OS was significantly prolonged in patients receiving HMA as compared to BSC (1.1 vs. 0.6 years, p<0.01). This was also observed for the risk of AML-transformation in this subgroup of patients: The median time to AML was 1.8 years in HMA-treated patients versus 0.6 years in BSC (p=0.012). Conclusions: To our knowledge, the study describes the largest patient cohort with MDS/AML and monosomy 7 published to date. Further data regarding the clinical characteristics of this subgroup of patients and the treatment regimes applied will be presented in detail. The study was supported by research funding from Celgene Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Schanz: Celgene: Honoraria, Research Funding, Travel grants: Celgene, Novartis, Lilly Other. Götze:Celgene Corp, Novartis Pharma: Honoraria. Nolte:Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants Other.

High Prevalence of Relapse in Australian Children with Ph-like Acute Lymphoblastic Leukemia Despite Risk Adapted Treatment

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1419-1419 ◽  
Author(s):  
Susan L Heatley ◽  
Teresa Sadras ◽  
Eva Nievergall ◽  
Chung Hoow Kok ◽  
Phuong Dang ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Risk Groups ◽  
High Risk Group ◽  
Event Free Survival ◽  
Free Survival ◽  
Kaplan Meier ◽  
Medium Risk

Abstract Introduction: While remission rates for childhood acute lymphoblastic leukemia (ALL) now exceed 80%, relapsed ALL remains the leading cause of non-traumatic death in children. Recently, a high-risk group of B-progenitor ALL patients has been identified. Such cases exhibit a gene expression profile similar to that of BCR-ABL1 positive (Ph+) ALL but are BCR-ABL1 negative, and also experience poor treatment outcomes. This subset, termed Ph-like ALL, is characterised by a range of genetic alterations that activate cytokine receptor and kinase signalling, allowing potential targeting by available tyrosine kinase inhibitors (TKI). The frequency of Ph-like ALL in the Australian community and the prognosis in the setting of the first MRD (minimal residual disease) intervention trial by the Australian and New Zealand Children's Haematology/Oncology Group (ANZCHOG ALL8) is unknown. Method: We retrospectively screened 250 unselected samples that were available from children diagnosed with B-ALL, for Ph-like ALL. The children, aged between 1 and 18 years, were enrolled on the ANZCHOG ALL8 trial and recruited from 2002-2011. The criteria for stratification to the high-risk group, based upon Berlin-Frankfurt-Munster (BFM) protocols, were BCR-ABL1 or MLL t(4;11) translocation; poor prednisolone response at day 8; failure to achieve remission by day 33 or high MRD (>5 x10-4) at day 79. MRD was measured by RQ-PCR for patient-specific immunoglobulin and T-cell receptor rearrangements. All patients received a standard BFM four drug induction chemotherapy regimen including a prednisolone pre-phase and intrathecal methotrexate. High-risk patients received a further three novel intensive blocks of chemotherapy followed by transplant in most cases. Patients were screened for Ph-like ALL using a custom Taqman Low Density Array (TLDA) based upon previous reports. Fusions were then confirmed by RT-PCR for 30 known fusions, Sanger sequencing, mRNA sequencing and/or FISH. Results: Ten percent (25/250) of children in this cohort were identified as having Ph-like ALL, with most fusions converging on kinase activating pathways (Table 1). Three Ph-like ALL patients were considered high-risk, the remaining 22 (88%) were medium risk. Five children with Ph-like ALL, that did not have a fusion identified by RT-PCR, are currently under further investigation. Furthermore, 15 of the 20 (75%) of rearrangements involved CRLF2 with 10 (66%) of these children relapsing. Strikingly, 56% (14/25) of children in the ALL8 cohort who were identified as Ph-like subsequently relapsed compared to 16% (36/225) who were not, with significantly worse event free survival (p<0.0001) (Figure 1). Conclusion: Here we demonstrate a significantly higher frequency of relapse amongst Australian children with Ph-like ALL compared to non Ph-like disease despite a MRD-adjusted intensification regimen. In this cohort, these children should be classified as high-risk due to high treatment failure rates with standard/medium risk regimens. Importantly, rapid identification of these patients may guide future intervention with targeted therapies, such as TKI, matched to the causative genetic lesion in this high-risk group. Figure 1. Fusions identified in Ph-like ALL from ANZCHOG ALL8 cohort. Figure 1. Fusions identified in Ph-like ALL from ANZCHOG ALL8 cohort. Figure 2. Kaplan-Meier estimates of event free survival for patients with Ph-like ALL and non Ph-like ALL (all risk groups). Figure 2. Kaplan-Meier estimates of event free survival for patients with Ph-like ALL and non Ph-like ALL (all risk groups). Disclosures Hughes: ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mullighan:Incyte: Consultancy, Honoraria; Cancer Science Institute: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Speakers Bureau; Loxo Oncology: Research Funding. White:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

scholarly journals The HAS-RISC Score for Venous Thromboembolism (VTE) Risk Stratification in Newly Diagnosed Multiple Myeloma Patients Starting Immunomodulatory Drugs (IMID)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 144-144 ◽  
Author(s):  
Ang Li ◽  
Qian V. Wu ◽  
Greg Warnick ◽  
Neil A Zakai ◽  
Edward N. Libby ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Assessment ◽  
High Risk ◽  
Research Funding ◽  
Risk Group ◽  
High Risk Group ◽  
Assessment Model ◽  
Risk Assessment Model ◽  
Newly Diagnosed ◽  
Very High

Abstract Introduction: Patients with newly diagnosed multiple myeloma (MM) have high risk of venous thromboembolism (VTE) when starting initial treatment that contains immunomodulatory drugs (IMID) such as lenalidomide or thalidomide. The National Comprehensive Cancer Network (NCCN) guideline recommends primary anticoagulant thromboprophylaxis for the high-risk patients. However, it is challenging to risk-stratify patients without a validated risk model. We have conducted a retrospective cohort study using the SEER-Medicare (Surveillance, Epidemiology, and End Results) database to derive a new VTE risk assessment model. Methods: We selected all patients 66 or older with newly diagnosed MM 2007 to 2013. Patients were included if they had a prescription of IMID within twelve months of diagnosis and complete enrollment for fee-for-service and prescription drug coverage. We ascertained baseline demographics and VTE risk factors from the current NCCN guideline using validated codes. The VTE outcome was defined as either one inpatient or two outpatient claims at least 30 days apart in combination with an anticoagulant prescription within 90 days. All patients were followed from the date of IMID initiation until first VTE occurrence or death and were censored for disenrollment from Medicare, discontinuation of IMID (after a grace period of 90 days), autologous transplantation, or the end of claims data (12/31/2014). Cause specific Cox regression models were used for time to VTE analysis. For variable selection, all risk factors with p-value <0.10 were considered candidates for inclusion in the final multivariable regression model. VTE history, recent surgery, and anticoagulant exposure were forced into the model, regardless of significance testing. Integer points were assigned according to the beta coefficients and subsequent risk groups were created. The model's discrimination was validated internally by the bias-corrected Harrell's c statistic and the 95% confidence interval was estimated from 200 bootstrap samples. Results: We identified 2397 MM patients on IMID that met the study criteria. The median time on IMID treatment was 116 days (IQR 28-279). The mean age of patients was 74, 49% were female, 80% were White, 13% were Black, 6.5% were Asian. Only 13% of patients had concurrent anticoagulant exposure (11% warfarin, 2% LMWH, 1% DOAC) with a median duration of 116 days (IQR 42-315 days). In the multivariable model built from candidate covariates, we identified history of VTE, recent surgery, cytotoxic (non-bortezomib) chemotherapy, higher dose dexamethasone, older age, and Black race, as important risk factors. Asian race and LMWH/DOAC use were associated with lower VTE risk (Table 1). We derived a risk assessment model that stratified patients into 2 prognostic risk groups (Table 1): 25% (n=581) in the very high-risk group (score 2 to 7), 75% (n=1816) in the standard-risk group (score -3 to 1). The incidence of VTE at 3 months and 6 months were 9.5% and 16.3% in the very high-risk group compared to 3.7% and 6.3% in the standard-risk group with a resulting hazard ratio of 2.73 (p<0.001) (Figure 1). The bias-corrected Harrell's c statistic for the product index was 0.63 (0.59-0.68). Conclusions: We have derived a VTE risk assessment model specifically for patients with MM starting IMID therapy. The HAS-RiSC score combines 7 clinical risk factors - History of VTE, Age 80+, Surgery within last 90 days, Race Black, race Asian, Steroid use, and Chemotherapy - into a simplified VTE risk assessment model that identifies a subgroup of patients at very high risk for VTE. External validation of this risk assessment model is currently in progress. Disclosures Garcia: Daiichi Sankyo: Research Funding; Incyte: Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy; Retham Technologies LLC: Consultancy; Shingoi: Consultancy; Portola: Research Funding; Bristol Meyers Squibb: Consultancy; Boehringer Ingelheim: Consultancy. Lyman:Amgen: Other: Research support; Generex Biotechnology: Membership on an entity's Board of Directors or advisory committees; Halozyme; G1 Therapeutics; Coherus Biosciences: Consultancy.

scholarly journals Hematopoietic Cell Transplant-Composite Risk (HCT-CR) — a Novel Prognostic Model to Predict Transplant Outcomes

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2141-2141
Author(s):  
Piyanuch Kongtim ◽  
Simrit Parmar ◽  
Denái R. Milton ◽  
Jorge M. Ramos Perez ◽  
Gabriela Rondon ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Research Funding ◽  
Risk Group ◽  
High Risk Group ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Composite Risk ◽  
Very High

Abstract Introduction Outcomes after allogeneic stem cell transplant (AHSCT) are influenced by both disease and patient related factors. We hypothesized that combining hematopoietic stem cell transplant comorbidity-age index (HCT-CI/Age) and the refined disease risk index (DRI-R) would better predict survival post-transplant and developed a hematopoietic cell Transplant-composite risk (HCT-CR) model, which we tested in a group of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) treated at MD Anderson Cancer Center (MDACC). Methods The study included consecutively treated patients, 18 years of age or older, with AML and MDS who received first AHSCT at MDACC between 2005-2016. Donors were HLA-matched related (MRD), HLA-matched unrelated (MUD), 9/10 MUD (MMUD), haploidentical (HAPLO) and 9/10 MRD (MMRD). To develop this model, patients were assigned into 4 groups: 1. Patients with low/intermediate DRI-R and HCT-CI/Age </=3 (low-risk); 2. Patients with low/intermediate DRI-R and HCT-CI/Age >3 (intermediate-risk); 3. Patients with high/very high DRI-R and HCT-CI/Age </=3 (high-risk); and 4. Patients with high/very high DRI-R and HCT-CI/Age >3 (very high-risk). Primary endpoint was 5-year overall survival (OS); other outcomes assess were progression-free survival (PFS), non-relapse mortality (NRM) and relapse rate. The stability of the HCT-CR model was tested by bootstrap resampling. The discrimination power of the HCT-CR model on OS was compared with that of the DRI-R, HCT-CI/Age and cytogenetic risk model by the Harrell C-concordance index. Results The analysis included 942 patients (492 male and 450 female) with a median age of 53 years (range 18-65 years). Cytogenetic data at diagnosis was available in 928 (98.5%) patients and was favorable, intermediate and adverse cytogenetic risk in 63 (7%), 523 (56%) and 342 (37%), respectively. Fifty-five (6%), 399 (43%), 392 (42%) and 82 (9%) patients had low, intermediate, high and very high DRI-R, respectively. The HCT-CI/Age was available in 922 (98%) patients with the median score of 3 (range 0-18). Donor types included MRD (n=377), MUD (n=416), MMUD (n=68), HAPLO (n=73) and MMRD (N=8). Using the HCT-CR model, patients were stratified into 4 risk groups: low (N=272), intermediate (N=168), high (N=284) and very high-risk (N=184), with significantly different survival. The 5-year OS rates for patients in low, intermediate, high and very high-risk group were 57%, 48%, 34%, and 26%, respectively (P<0.001) (Figure 1). The probability of 5-year PFS rates were 55%, 46%, 30% and 23% for these 4 risk groups, respectively (P<0.001). Post-transplant outcomes of all 4 HCR-CR groups are summarized in Table 1. Compared with the low HCT-CR risk group, patients with intermediate, high and very high-risk group had a significantly increased risk of death with HR of 1.42 (95%CI 1.06-1.91; P=0.02), 2.11 (95%CI 1.65-2.70; P<0.001), and 3.02 (95%CI 2.32-3.92; P<0.001), respectively. The significant association between OS and the HCT-CR groups persisted after adjusting for potential confounders with adjusted HR of 1.37 (95%CI 1.02-1.85) for intermediate, 2.08 (95%CI 1.62-2.67) for high and 2.92 (95%CI 2.23-3.82) for very high-risk group when compared with low risk group. The stability of the hematopoietic cell transplant - composite risk model was confirmed in a bootstrap resampling procedure. Among 500 new datasets, on average, patients in intermediate, high and very high-risk group had significantly increased risk of death after transplant when compared with low risk group with HR of 1.39, 2.11 and 2.98, respectively. Results from the concordance test showed that the HCT-CR model provided better discriminative capacity for prediction of OS when compared with DRI-R, HCT-CI/Age and cytogenetic risk group models with C-index of 0.62 versus 0.60, 0.54 and 0.55, respectively. The goodness of fit test showed that the HCT-CR model fit the data significantly better than the other models (P<0.001). Conclusion Combining disease and patient-related factors provides better survival stratification for patients with AML/MDS receiving AHSCT. This novel HCT-CR model will be validated in patients with all diseases undergoing allogeneic hematopoietic stem cell transplantation and results will be presented at the meeting. Disclosures Oran: ASTEX: Research Funding; Celgene: Consultancy, Research Funding; AROG pharmaceuticals: Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.

Allogeneic Transplantation (HCT) for Myelodysplastic Syndrome:Recent MDACC Experience.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1131-1131
Author(s):  
Uday Popat ◽  
Marcos J de Lima ◽  
Touch Ativitavas ◽  
Gabriela Rondon ◽  
Leandro de Padua Silva ◽  
...  
Keyword(s):  
High Risk ◽  
Median Time ◽  
Cumulative Incidence ◽  
Risk Group ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
High Risk Group ◽  
Hla Typing ◽  
Unrelated Donor ◽  
Very High

Abstract BACKGROUND: Many recent advances have occurred in the field of MDS including hypomethylating agents, lenalidomide, and WHO classification. Likewise the field of HCT has also undergone major new developments including non ablative conditioning, better supportive care, better HLA typing, selection of unrelated donors and development of reduced toxicity ablative regimens like Busulfan and Fludarabine. The role of HCT therefore needs to be redefined in light of these developments. The purpose of this study is to report our recent results. PATIENTS AND METHODS: 89 consecutive patients with MDS as defined by WHO criteria treated at our institution between Jan 2002 and April 2008 are included in this report. There were 60 males and 29 female with a median age of 54 (23–67). There were 5(6%) patients with RA, 1(1%) RARS, 9(10%) RCMD, 22(25%) RAEB 1, 17(19%) RAEB 2, and 35(39%) therapy related MDS(t MDS). Their IPSS scores were 25(28%) patients with Intermediate 1, 49(55%) Intermediate 2, 15(17%) high. Their WPSS categories were 5(6%) patients Low, 9(10%) Intermediate, 49(55%) high, and 26(29%) very high. 51(57%) patients had a matched related donor and 38(43%) had an unrelated donor. Conditioning regimen were Flu/Bu in 56(63%) patients, Bu/Cy 1(1%), Flu/Mel 32(36%). According to HCT-CI index, the comorbidity scores were 0 in 16(18%) patients, 1 or 2 in 19(21%) and greater then 2 in 54(61%). Median time from diagnosis to transplant was 8 months (range 1–51 months). RESULTS: With a median follow up of 28 (3–73) months, 2 year overall(OS) and disease free survival were 54%(95% CI; 42%–66%) and 52%(95% CI; 40%–64%) respectively. Cumulative incidence of non relapse mortality at 2 years was 23% (95% CI; 16%–35%). Cumulative incidence of relapse mortality at 2 years was 23% (95% CI; 15%–34%). As per WHO grouping, OS was 63%, 60%, 46% and 48% in patients with Low blast count (RA, RARS, RAMD), RAEB1, RAEB2 and t MDS( p=0.46) respectively. WPSS score was significantly(P=0.01) predictive of overall survival (see fig): 27% surviving in very high risk group, 61% in high risk group and 78% in Low and intermediate risk group. Likewise cytogenetic risk group and IPSS were significantly predictive of survival. Donor type or graft source did not predict outcome. Five patients developed primary(3) or secondary(2) graft failure. Median time to neutrophil engraftment was 13 days (8–26 days) and to platelet engraftment was 16 days (9–89 days). CONCLUSION: These results in patients with comorbidities and with a median age of 54 years are promising. Cytogenetics and prognostic scores based on cytogenetics predict outcome after HCT. Figure Figure

The Utility Of Newer Risk Models In Predicting Outcomes Of Patients (pts) With Higher-Risk (HR) Myelodysplastic Syndromes (MDS) Treated With Azactidine (aza)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2771-2771
Author(s):  
Amer M. Zeidan ◽  
Najla H Al Ali ◽  
Mohamed A. Kharfan-Dabaja ◽  
Eric Padron ◽  
Ling Zhang ◽  
...  
Keyword(s):  
High Risk ◽  
Scoring System ◽  
Research Funding ◽  
Goodness Of Fit ◽  
Risk Group ◽  
Risk Groups ◽  
High Risk Group ◽  
Information Criteria ◽  
Prognostic Groups ◽  
Very High

Abstract Background While aza is the only drug shown to prolong survival in MDS, only half of aza-treated pts achieve objective responses (10-20% complete remission), and 4-6 months might be needed before a response is seen. Therefore the ability to select pts with high and low likelihoods of benefit from aza therapy is a clinical and a research priority. No clinical or laboratory parameter consistently predicts response or survival with aza therapy. A French prognostic scoring system (FPSS) was proposed to predict survival among aza-treated pts with HR-MDS. We sought to compare the relative prognostic discriminatory power of the FPSS with that of the revised IPSS (IPSS-R) and the global MD Anderson prognostic scoring system (MDAPSS) in a large cohort of aza-treated pts with IPSS HR-MDS. Methods The MDS database at Moffitt Cancer Center (MCC) was used to identify patients with HR-MDS (International Prognostic Scoring System [IPSS] intermediate-2 [INT-2] and high-risk) who received aza therapy. Kaplan-Meier curves were used to depict survivals, and the log-rank test was used to compare median overall survival (OS). Akaike information criteria (AIC) were used to assess the relative goodness of fit of the models. Results We identified 259 patients HR-MDS (74.1% with INT-2 and 25.9% with high IPSS) treated with aza at the MCC. The median duration of follow up since diagnosis was 53 months (M) (95% confidence interval [CI], 49-59 M). The median number of aza cycles was 5 (range 1-72), with 75% of pts receiving 4 cycles of therapy or more. The median time from diagnosis to aza initiation was 1.5 M. The median OS for the entire cohort was 19 M (95%CI, 16-22 M), 64% of pts were males, 91% were white, 80% were older than 60 years, and 25% had therapy-related MDS. For the IPSS, the median OS was 23.5 M (CI, 18.4-28.6 M) for INT-2 and 15.9 M (CI, 13.6-18.2 M) for high-risk group (P=0.004). For the FPSS, the median OS was 29.5 M (CI, 14.1-44.9 M) for low risk (LR), 21.1 M (CI, 16.4-26.0 M) for intermediate risk (IR), and 14.1 M (CI, 8.7-19.5 M) for HR (P=0.001). For the MDAPSS the median OS was not reached (NR) for low, 53.5 M (CI, 37.5-69.4 M) for INT-1, 29.5 M (CI, 18.3-40.6 M) for INT-2, and 16.1 M (CI, 14.5-17.7 M) for high risk groups (P<0.0001). For the IPSS-R, the median OS 40.6 M (CI, 22.8-58.4 M) for low, 44.7 M (CI, 25.0-64.4 M) for INT, 23.5 M (CI, 20.3-26.8 M) for high, and 15.2 M (CI, 13.7-16.8 M) for very-high risk groups (P<0.0001). Scores generated using AIC to assess the relative goodness of fit (lower is better) were 1453 (IPSS-R), 1480 (MDAPSS), 1512 (FPSS), and 1522 (IPSS). The IPSS could not refine any of the other models. All three newer models refined IPSS INT-2 but not IPSS high-risk. The IPSS did not refine any of the newer models. The MDAPSS refined the FPSS LR and IR and the IPSS-R high and very-high groups. The FPSS refined IPSS-R very high risk group but not the not the MDAPSS. The R-IPSS did not refine the MDAPSS or the FPSS. Response rates were not statically significantly different within the prognostic groups in any of the scoring systems. Conclusions The IPSS-R, MDAPSS, and the FPSS all functioned well to separate aza-treated pts with IPSS HR-MDS into prognostic groups with different survivals, but the IPSS-R and MDAPSS appear superior to the FPSS. None of the prognostic systems predicted response to aza therapy. HR-MDS patients with poor projected survival with aza therapy might be considered for experimental approaches. Disclosures: Off Label Use: entinostat for MDS. Lancet:Celgene: Research Funding. List:Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau.

scholarly journals Immunogenomic Gene Signature of Cell-Death Associated Genes with Prognostic Implications in Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 155
Author(s):  
Pankaj Ahluwalia ◽  
Meenakshi Ahluwalia ◽  
Ashis K. Mondal ◽  
Nikhil Sahajpal ◽  
Vamsi Kota ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
High Risk ◽  
Lung Adenocarcinoma ◽  
Risk Group ◽  
High Risk Group ◽  
Free Survival ◽  
Cell Death Pathways

Lung cancer is one of the leading causes of death worldwide. Cell death pathways such as autophagy, apoptosis, and necrosis can provide useful clinical and immunological insights that can assist in the design of personalized therapeutics. In this study, variations in the expression of genes involved in cell death pathways and resulting infiltration of immune cells were explored in lung adenocarcinoma (The Cancer Genome Atlas: TCGA, lung adenocarcinoma (LUAD), 510 patients). Firstly, genes involved in autophagy (n = 34 genes), apoptosis (n = 66 genes), and necrosis (n = 32 genes) were analyzed to assess the prognostic significance in lung cancer. The significant genes were used to develop the cell death index (CDI) of 21 genes which clustered patients based on high risk (high CDI) and low risk (low CDI). The survival analysis using the Kaplan–Meier curve differentiated patients based on overall survival (40.4 months vs. 76.2 months), progression-free survival (26.2 months vs. 48.6 months), and disease-free survival (62.2 months vs. 158.2 months) (Log-rank test, p < 0.01). Cox proportional hazard model significantly associated patients in high CDI group with a higher risk of mortality (Hazard Ratio: H.R 1.75, 95% CI: 1.28–2.45, p < 0.001). Differential gene expression analysis using principal component analysis (PCA) identified genes with the highest fold change forming distinct clusters. To analyze the immune parameters in two risk groups, cytokines expression (n = 265 genes) analysis revealed the highest association of IL-15RA and IL 15 (> 1.5-fold, p < 0.01) with the high-risk group. The microenvironment cell-population (MCP)-counter algorithm identified the higher infiltration of CD8+ T cells, macrophages, and lower infiltration of neutrophils with the high-risk group. Interestingly, this group also showed a higher expression of immune checkpoint molecules CD-274 (PD-L1), CTLA-4, and T cell exhaustion genes (HAVCR2, TIGIT, LAG3, PDCD1, CXCL13, and LYN) (p < 0.01). Furthermore, functional enrichment analysis identified significant perturbations in immune pathways in the higher risk group. This study highlights the presence of an immunocompromised microenvironment indicated by the higher infiltration of cytotoxic T cells along with the presence of checkpoint molecules and T cell exhaustion genes. These patients at higher risk might be more suitable to benefit from PD-L1 blockade or other checkpoint blockade immunotherapies.

Abstract 14084: Albuminuria and Prognosis Among Individuals With Atherosclerotic Cardiovascular Disease: The Atherosclerosis Risk in Communities (aric) Study

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yejin Mok ◽  
Shoshana Ballew ◽  
Richard Stacey ◽  
Joseph Rossi ◽  
Silvia Koton ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
High Risk ◽  
Kidney Function ◽  
Risk Group ◽  
High Risk Group ◽  
Composite Outcome ◽  
Clinical Conditions ◽  
Reduced Kidney Function ◽  
Aric Study ◽  
Very High

Background: The AHA/ACC 2018 Cholesterol Guideline categorizes ASCVD patients into very high-risk vs. high-risk to guide intensive therapy. This categorization is based on clinical conditions, including reduced kidney function, but does not take into account albuminuria, the other kidney measure often available in clinical practice. Methods: We studied 838 participants with major ASCVD (myocardial infarction, ischemic stroke, or symptomatic peripheral artery disease) from the ARIC study at baseline (1996 - 98). We compared urine albumin-to-creatinine ratio (ACR) and the eight high-risk conditions of age 65+, reduced kidney function, diabetes, etc. in the AHA/ACC Guideline regarding their associations with composite outcome of all-cause mortality, myocardial infarction, ischemic stroke, and heart failure. We also evaluated risk classification by adding ACR to the eight high-risk conditions. Results: During a median follow-up of 8 years, 724 (86%) participants developed a composite outcome. ACR ≥30 mg/g was associated with the composite outcome (adjusted hazard ratio [aHR] 1.45 [95% CI 1.20, 1.75]) beyond the eight high-risk conditions (aHR of these conditions ranged from 0.96 to 2.46). The addition of ACR improved the c-statistic by 0.011 (95% CI 0.003-0.019) from 0.661 to 0.672. ACR classified 4.6% of high-risk group to very high-risk and 11.2% of very high-risk group to extremely very high-risk with a reasonable calibration (Figure). Even ACR ≥10 mg/g showed a significant aHR of 1.38 (1.17, 1.63) and classified 13.4% of high-risk and 18.1% very high-risk to a higher risk category. Of our patients with ASCVD, 77% had diabetes, hypertension, or low kidney function, clinical conditions in which the ACR assessment is recommended. Conclusions: In ASCVD, albuminuria was a strong predictor of major adverse cardiovascular outcome and improved risk prediction. Clinicians should pay attention to albuminuria, in addition to eGFR, when managing ASCVD patients.

Stem Cell Transplantation in Elderly Patients with Acute Lymphoblastic Leukemia (ALL) in First Complete Remission (CR1).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1966-1966
Author(s):  
Renate Arnold ◽  
Dietrich Beelen ◽  
Martin Bornhaeuser ◽  
Donald Bunjes ◽  
Juergen Finke ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
High Risk ◽  
Elderly Patients ◽  
Risk Group ◽  
High Risk Group ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Conditioning Regimens ◽  
Very High

Abstract In the German Multicenter ALL studies (GMALL) patients aged &gt;55 years with high risk (B-lineage ALL with WBC at diagnosis &gt;30000, late CR, t (4; 11), complex aberrant karyotype or prae-T or mature T-ALL) or very high risk (Ph+/BCR-ABL+) ALL are increasingly candidates for allogeneic stem cell transplantation (allogeneic SCT with a HLA identical sibling donor, MRD or a matched unrelated donor, MUD) or autologous SCT. Here, we report on 31 elderly patients transplanted within the GMALL studies 06/99 and 07/03. Median age of the patients was 61 years (56–65). 22 patients belonged to the very high risk group (VHR), 8 patients to the high risk group (HR) and 1 patient from the standard risk group (SR) was transplanted because of detection of minimal residual disease.17/31 patients were transplanted from a matched unrelated donor, 9/31 patients from a HLA identical sibling donor and 5/31 patients underwent autologous SCT. Conditioning regimens for MRD SCT were myeloablative (MAC) in 6 patients (TBI 12 Gy and chemotherapy n=2, radioimmunotherapy + chemotherapy n=2, chemotherapy only n=2) and 3 patients received reduced intensity conditioning (RIC).Conditioning regimens for MUD SCT changed over time with an increasing number of RIC in the study 07/03. In total, 7/17 patients received MAC (TBI 12 Gy and chemotherapy n=5, chemotherapy only n=2) and 10/17 patients received RIC. Conditioning regimens in autologous SCT were myeloablative (MAC) in 5/5 patients. Results: After allogeneic MRD SCT 4/9 patients (44%) are alive in CCR (d+ 24, d+ 611, d+ 1721, d+ 2321), 3/9 patients died due to leukemia, 2/9 due to transplant related mortality (TRM). After allogeneic MUD SCT 8/17 patients (46%) are alive in CCR (from d+ 165 to d+ 2176). 1 further patient is alive after re- SCT for treatment of relapse. 7/17 patients died due to TRM and 1 patient died due to relapse. After autologous SCT 2/5 patients are alive in CCR (d+ 1703, d+ 1731), 3/5 died due to relapse. Risk factors for TRM: In allo SCT and MAC 8/13 patients died due to TRM in contrast to 1/13 patients with RIC. In auto SCT none of the patients died due to TRM. Risk factors for relapse: In allogeneic MRD SCT 3/9 patients died due to relapse and 2/17 patients relapsed after MUD SCT. Due to the small number of patients, no difference between MAC and RIC could be found. In autologous SCT 3/5 patients died due to relapse. In conclusion: The study shows that allo MRD but also MUD SCT is very effective in a selected population of elderly ALL patients. Since the survival of elderly patients with chemotherapy only is about 25%, more patients should be encouraged to have a MRD or MUD SCT.

Application of a Validated Predictive Model for Venous Thromboembolism in Cancer to Patients with Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 534-534
Author(s):  
Natasha Catherine Edwin ◽  
Jesse Keller ◽  
Suhong Luo ◽  
Kenneth R Carson ◽  
Brian F. Gage ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Risk Group ◽  
High Risk Group ◽  
Low Risk ◽  
Intermediate Risk ◽  
Discriminative Ability ◽  
Blood Institute ◽  
C Statistic

Abstract Background Patients with multiple myeloma (MM) have a 9-fold increased risk of developing venous thromboembolism (VTE). Current guidelines recommend pharmacologic thromboprophylaxis in patients with MM receiving an immunomodulatory agent in the presence of additional VTE risk factors (NCCN 2015, ASCO 2014, ACCP 2012). However, putative risk factors vary across guidelines and no validated VTE risk tool exists for MM. Khorana et al. developed a VTE risk score in patients with solid organ malignancies and lymphoma (Blood, 2008). We sought to apply the Khorana et al. score in a population with MM. Methods We identified patients diagnosed with MM within the Veterans Health Administration (VHA) between September 1, 1999 and December 31, 2009 using the International Classification of Diseases (ICD)-03 code 9732/3. We followed the cohort through October 2014. To eliminate patients with monoclonal gammopathy of undetermined significance and smoldering myeloma, we excluded patients who did not receive MM-directed therapy within 6 months of diagnosis. We also excluded patients who did not have data for hemoglobin (HGB), platelet (PLT) count, white blood count (WBC), height and weight, as these are all variables included in the Khorana et al. risk model. Height and weight were assessed within one month of diagnosis and used to calculate body mass index (BMI). We measured HGB, PLT count, and WBC count prior to treatment initiation: within two months of MM diagnosis. A previously validated algorithm, using a combination of ICD-9 code for VTE plus pharmacologic treatment for VTE or IVC filter placement, identified patients with incident VTE after MM diagnosis (Thromb Res, 2015). The study was approved by the Saint Louis VHA Medical Center and Washington University School of Medicine institutional review boards. We calculated VTE risk using the Khorana et al. score: We assigned 1 point each for: PLT ≥ 350,000/μl, HGB < 10 g/dl, WBC > 11,000/μl, and BMI ≥ 35 kg/m2. Patients with 0 points were at low-risk, 1-2 points were considered intermediate-risk and ≥3 points were termed high-risk for VTE. We assessed the relationship between risk-group and development of VTE using logistic regression at 3- and 6-months. We tested model discrimination using the area under the receiver operating characteristic curve (concordance statistic, c) with a c-statistic range of 0.5 (no discriminative ability) to 1.0 (perfect discriminative ability). Results We identified 1,520 patients with MM: 16 were high-risk, 802 intermediate-risk, and 702 low-risk for VTE using the scoring system in the Khorana et al. score. At 3-months of follow-up, a total of 76 patients developed VTE: 27 in the low-risk group, 48 in the intermediate-risk group, and 1 in the high-risk group. At 6-months of follow-up there were 103 incident VTEs: 41 in the low-risk group, 61 in the intermediate-risk group, and 1 in the high-risk group. There was no significant difference between risk of VTE in the high- or intermediate-risk groups versus the low-risk group (Table 1). The c-statistic was 0.56 at 3-months and 0.53 at 6-months (Figure 1). Conclusion Previously, the Khorana score was developed and validated to predict VTE in patients with solid tumors. It was not a strong predictor of VTE risk in MM. There is a need for development of a risk prediction model in patients with MM. Figure 1. Figure 1. Disclosures Carson: American Cancer Society: Research Funding. Gage:National Heart, Lung and Blood Institute: Research Funding. Kuderer:Janssen Scientific Affairs, LLC: Consultancy, Honoraria. Sanfilippo:National Heart, Lung and Blood Institute: Research Funding.

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