The Disease Risk Index Is a Robust Tool for Allogeneic Hematopoietic Stem Cell Transplantation Risk Stratification: An Independent Validation Study on a Large Cohort of the European Society for Blood and Marrow Transplantation (EBMT)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 988-988 ◽  
Author(s):  
Roni Shouval ◽  
Joshua Fein ◽  
Myriam Labopin ◽  
Nicolaus Kroger ◽  
Rafael F. Duarte ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Hematological Malignancies ◽  
Disease Risk ◽  
Risk Index ◽  
Risk Groups ◽  
Advisory Committees ◽  
Very High

Abstract Background: Allogeneic stem cell transplantation is a potentially curative procedure to a long list of hematological malignancies, but involves substantial risk of morbidity and mortality. Means for accurately predicting outcome and assessing risk are thus greatly needed. The Disease Risk Index (DRI) is a prognostic tool developed and validated by Armand et al. across a wide range of hematological malignancies (Blood 2012, Blood 2014) on cohorts of American patients. The Index stratifies patients into 4 distinct risk groups (low, intermediate, high, very high) and has yet to be validated in an international cohort. We sought to evaluate the validity of the DRI in a large cohort of European patients. Methods: This was a retrospective validation study on an independent cohort of patients undergoing allogeneic HSCT and reported the European Society for Blood and Marrow Transplantation (EBMT). Patients included had a hematological malignancy and underwent allogeneic transplantation between the years of 2000 and 2015. Risk groups were coded in accordance with the refined DRI (Blood, 2014). Outcomes were evaluated 4 years after the allogeneic HSCT. Overall survival (OS) was calculated with the Kaplan-Meier method. The log-rank test was used for comparisons of Kaplan-Meier curves. Cumulative incidence curves for nonrelapse mortality (NRM) and relapse with or without death were constructed reflecting time to relapse and time to NRM, respectively, as competing risks. The difference between cumulative incidence curves in the presence of a competing risk was tested with the Gray method. The prognostic effect of the DRI strata was estimated using a Cox proportional hazard model for OS and a Fine and Gray model for NRM and relapse. Results: A total of 89,061 patients from 423 transplantation centers were included in the analysis. Median age was 48.3 (IQR 36.2-57.5). The most frequent indication for transplantation was AML (39,530 patients) followed by ALL (16,206) and MDS (9,750); other indications spanned the spectrum of hematological malignancies. The majority of patients were in 1st or 2nd complete remission (54%). The median follow-up period was 3.6 years. Approximately 63% of patients were classified as intermediate risk by DRI, suggesting that this group could be further partitioned. The 4 year overall survival (95% CI) of the low, intermediate, high, and very high risk groups was 60.8% (59.9-61.8), 51.3% (50.8‐51.8), 27.0% (26.1‐27.8), 18.4% (17.1-19.8) (Figure 1). The same groups corresponded with increasing cumulative incidence of relapse; 8.9% (8.3-9.4), 19.3% (18.9-19.7), 39.0% (37.8-39.6), 45.1% (43.4-46.7), respectively. The DRI groups also showed increasing hazard between strata in the overall survival setting; intermediate risk was associated with a hazard ratio of 1.32, high risk 2.67 and very high risk 3.71 relative to low risk. Relapse showed a similar pattern. NRM was less strongly stratified by DRI (Table 1). The DRI groups maintained a similar risk, regardless of whether the transplantation was performed prior or after 2008. DRI was the strongest determinant of overall survival and relapse when introduced to a multivariable model with additional covariates. AUC for the index at 4 years was 62.5 for OS, 58.5 for NRM and 68.2 for relapse. Conclusions: We have validated the Disease Risk Index in a massive European data set. The groupings suggested by the DRI corresponded with distinct risk groups for overall mortality and relapse. Overall, our results indicate the international applicability of this robust prognostic tool. Figure 1. Kaplan-Meyer survival curves for overall survival, stratified by DRI Figure 1. Kaplan-Meyer survival curves for overall survival, stratified by DRI Table 1 Table 1. Disclosures Bader: Medac: Consultancy, Research Funding; Riemser: Research Funding; Neovii Biotech: Research Funding; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Bonini:Molmed SpA: Consultancy; TxCell: Membership on an entity's Board of Directors or advisory committees. Dreger:Gilead: Consultancy; Janssen: Consultancy; Novartis: Speakers Bureau; Gilead: Speakers Bureau; Novartis: Consultancy; Roche: Consultancy. Kuball:Gadeta B.V,: Membership on an entity's Board of Directors or advisory committees. Montoto:Roche: Honoraria; Gilead: Research Funding.

scholarly journals Overall Survival and Subgroup Analysis from a Randomized Phase III Study of Intravenous Rigosertib Versus Best Supportive Care (BSC) in Patients (pts) with Higher-Risk Myelodysplastic Syndrome (HR-MDS) after Failure of Hypomethylating Agents (HMAs)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 163-163 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Pierre Fenaux ◽  
Aref Al-Kali ◽  
Maria R. Baer ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Primary Endpoint ◽  
Research Funding ◽  
Phase Iii ◽  
Controlled Study ◽  
Advisory Committees ◽  
Phase Iii Study ◽  
Very High

Abstract Background: No approved treatment options are available to HR-MDS pts after HMA therapy. Study 04-21 (“ONTIME” trial) was a Phase III, randomized, controlled study of the efficacy and safety of rigosertib, a novel small molecule inhibitor of PI3-kinase and PLK pathways, in a heterogeneous population of MDS pts who had relapsed after, failed to respond to, or progressed during administration of HMAs. The study was conducted at 87 sites in the United States and 5 European countries. Methods:From Dec 2010 to Aug 2013, 299 HR-MDS pts [<30% bone marrow blasts (BMBL)] who had progressed on (37% of total enrollment), failed to respond to (25%), or relapsed after (38%) HMA treatment were stratified on BMBL count and randomized 2:1 to receive rigosertib (199 pts) or BSC (100 pts). Rigosertib was administered at 1800 mg/24 hr for 72-hr as a continuous intravenous (CIV) ambulatory infusion, every 2 weeks for the first 16 weeks, and then every 4 weeks. The primary endpoint was overall survival (OS), analyzed on an intention-to-treat (ITT) basis using the Kaplan-Meier method stratified on BMBL (5% to 19% vs. 20% to 30%). The trial had a 95% power to detect a 13-wk increase in median OS from 17 wks on BSC, with a 2-sided alpha = 0.05. The following results are based on 242 deaths: 161 in the rigosertib arm and 81 in the BSC arm. Results : Overall, the 2 arms were balanced in terms of baseline characteristics, with the majority of pts being male (66%), and White (82%). Age ranged from 50-90 yrs in the rigosertib arm and 55-86 years in the BSC arm (median, 74 yrs). The majority of pts (85%) had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. The median duration of the last HMA therapy was 8.8 months (mo) in the rigosertib arm and 10.3 mo in the BSC arm; 127 (64%) of rigosertib pts and 57% of BSC pts were classified as “primary HMA failure” (ie, they failed to respond to or progressed during HMA therapy, as defined by Prebet et al, J Clin Oncol, 2011). A 2.3-mo improvement in median OS was found in the overall (ITT) population (8.2 mo rigosertib vs. 5.9 mo BSC) (Figure 1). The ITT survival for rigosertib was similar to that noted in Phase I/II studies (35 weeks). The stratified log-rank p-value was 0.33. The stratified hazard ratio was 0.87, which was quite different from the ratio of medians (5.9/8.2 = 0.72), due to the fact that the 2 survival curves converged at 15 mo. Notably, among the 184 patients with primary HMA failure, the median OS was 8.6 mo in the rigosertib arm (N = 127) vs. 5.3 mo in the BSC arm (N = 57), HR= 0.69, p= 0.040 (Figure 2). Multivariate Cox regression, adjusting for pretreatment prognostic factors, showed little change in the treatment effect. The following subgroups were correlated with better OS: pts with failure of/progression on HMA treatment, pts with duration of HMA treatment ≤ 9 mo, pts < 75 years of age, and pts with very high risk per IPSS-R (Figure 3). Rigosertib was well tolerated, with a median dose intensity of 92%. There were no significant compliance or operations issues related to ambulatory continuous infusion. Protocol-defined dose reductions were reported in 5% of pts, with 24% experiencing dose delays of >7 days, mostly due to unrelated adverse events (AEs). No obvious differences between rigosertib and BSC were found in the incidence of AEs (rigosertib, 99%; BSC, 85%) or of ≥ Grade 3 AEs (rigosertib, 79%; BSC, 68%). In the rigosertib arm, AEs reported by ≥ 20% of pts, irrespective of severity or causality, were nausea (35%), diarrhea (33%), constipation (31%), fatigue (30%), fever (27%), anemia (22%), and peripheral edema (21%). Rigosertib had low myelotoxicity, consistent with previous clinical experience. Conclusions:Although the primary endpoint in this Phase III study of rigosertib vs BSC in pts with HR-MDS did not reach statistical significance in the ITT population, encouraging rigosertib treatment-related improvement in OS was noted in several subgroups of MDS pts, including those with “primary HMA failure and in patients in the IPSS-R Very High Risk category. CIV therapy with rigosertib had a favorable safety profile in this orphan population of elderly pts with MDS. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Fenaux: Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Roboz:Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Astra Zeneca: Consultancy; Sunesis: Consultancy; Teva Oncology: Consultancy; Astex: Consultancy. Wilhelm:Onconova Therapeutics, Inc: Employment, Equity Ownership. Wilhelm:Onconova Therapeutics, Inc: Employment. Azarnia:Onconova Therapeutics, Inc: Employment. Maniar:Onconova Therapeutics, Inc: Employment.

Myeloablative Timed Sequential Busulfan Is Safe in Older Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3859-3859 ◽  
Author(s):  
Uday R. Popat ◽  
Patricia S Fox ◽  
Roland Bassett ◽  
Julianne Chen ◽  
Benigno C. Valdez ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Older Patients ◽  
Disease Risk ◽  
Risk Index ◽  
Fixed Dose ◽  
Cox Regression Analysis ◽  
Risk Of Death ◽  
Antileukemic Effect ◽  
Very High

Abstract Background: Reduced intensity conditioning regimen (RIC) extends allogeneic hematopoietic cell transplantation (HCT) to older patients and patients with comorbidities. Compared to myeloablative (MA) conditioning, RIC has higher rate of relapse but lower rate of non-relapse mortality (NRM), resulting in similar survival. BMT CTN is conducting a prospective study to compare these two approaches. To further improve survival for older patients, a MA regimen with low NRM is needed. Timed sequential therapy (TST), giving two courses of chemotherapy 1 week apart, has higher antileukemic effect in in-vitro and in-vivo in studies of patients with AML, including phase 3 studies. We hypothesized that MA dose of busulfan delivered per principles of TST enhances antileukemic effect without increasing toxicity. We therefore designed a study to test safety of two MA schedules of busulfan targeting busulfan exposure (AUC) of 16000 μmol.min and 20000 μmol.min. AUC of 20000 μmol.minis close to total average drug exposure achieved with IV busulfan fixed dose of 12.8mg/kg. Methods: Patients were randomized to receive total busulfan exposure of 16,000 μmol.min(16K) or 20,000 μmol.min( 20K). Patients received IV busulfan 80 mg/m2 per day on day -13 and -12 in outpatient clinic, fludarabine 40 mg/m2 day x 4 (day -6 to -3) and IV busulfanx 4 (day -6 to -3). Busulfan was dosed to achieve target AUC of 16K or 20K based on pharmacokinetic studies done on day -13 and day -6. GVHD prophylaxis was Tacrolimus (day -2 onwards) and mini dose methotrexate-5mg/m2 on day 1, 3, 6, and 11. Stem cells were infused on day 0. Primary endpoint of the study was to compare 100 day non-relapse mortality in two arms with stopping rules built in for safety. Patients with hematological malignancies were eligible for the study if they had adequate organ function and 8/8 matched related or unrelated donor. We enrolled patients on this study who were suitable for RIC. When the study began, upper age limit for eligibility was 70 years, but this was increased to 75 years during the course of the study as safety was established. Fisher’s exact test was used to compare toxicity and NRM rates between arms. Cox proportional hazards regression was used to estimate the effects of clinical variables on overall survival. Results: 97 patients were enrolled on the study until the DSMB stopped the randomization and permitted continued accrual onto the higher dose arm with busulfan AUC of 20,000 μmol.min. 49 were randomized to busulfan AUC of 16K and 48 to 20K. For all patients, median age was 60 (18-75) years. 3 (2%) patients were less than 40 years of age, 12 (12%) 40-49, 33 (34%) 50-59, 39 (40%) 60-69, and 10 (10%) 70-79 years. 53 patients had AML/MDS, 24 CML/MPD, 16 myeloma, and 4 lymphoid malignancies. Based on revised disease risk index, 3 had low risk, 53 intermediate risk, 35 high risk, and 6 very high risk disease. Donor was related for 43 and unrelated for 54. Comorbidity scores were 0 in 23, 1-2 in 24, and ≥ 3 in 50. With a median follow up of 9.2 months (range 1.8-24) in surviving patients, 100 day NRM was similar in two groups, 4% in 16K and 6% in 20K (p=0.68). Maximum toxicity per patient was not significantly different between arms (Table 1, p=0.37). The 1-year unadjusted survival rates (95% CI) in combined disease risk indexes low and intermediate vs high and very high were 67 (50-79)% and 38 (19-57)%, respectively for all 97 patients. Multivariable Cox regression analysis for overall survival showed increased risk of death for older age (HR 1.05; p=0.03), comorbidity 3 and higher (HR 1.89 p=0.08), and high or very high risk index (HR 2.04; p= 0.05). After also accounting for donor relation and cell type, Bu AUC of 20k showed improved overall survival and a 50% reduction in the risk of death (HR 0.50, P= 0.058). Table 1. Maximum grade of toxicity per patient, N (Row %) MaximumGrade per Patient AUC=16k AUC=20k Total p-value 5 7 (54%) 6 (46%) 13 0.37 4 6 (50%) 6 (50%) 12 3 23 (44%) 29 (56%) 52 2 11 (73%) 4 (27%) 15 1 2 (40%) 3 (60%) 5 Total Patients 49 48 97 Conclusion: Myeloablative timed sequential busulfan regimen is safe in older patients and patients with comorbidities. The regimen with busulfan AUC of 20,000 μmol.min appears promising and needs to be studied further. Disclosures Popat: Otsuka: Research Funding. Off Label Use: Busulfan.

Age-Adjusted Co-Morbidity Score - but Not Revised Disease Risk Index - Is Associated with Progression-Free Survival after Intermediate Intensity Double Unit CBT in Adults with Hematologic Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3231-3231
Author(s):  
Satyajit Kosuri ◽  
Patrick Hilden ◽  
Sean Devlin ◽  
Yeon Yoo ◽  
Emily Lauer ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Disease Risk ◽  
Risk Index ◽  
Progression Free Survival ◽  
Hematologic Malignancies ◽  
Free Survival ◽  
Kaplan Meier ◽  
Co Morbidity ◽  
Very High

Abstract Introduction: CB transplantation (CBT) after intermediate intensity conditioning is a less toxic alternative to CBT after high dose myeloablation. However, determinants of progression-free survival (PFS) and the impact of the pre-transplant revised Disease Risk Index (rDRI) and age-adjusted Hematopoietic Cell Transplant Co-morbidity Index (aaHCT-CI) are not established. Methods: We evaluated 2-year PFS in double-unit CBT (dCBT) recipients with hematologic malignancies who were conditioned with a myeloablative but intermediate intensity regimen of cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 5-10 mg/kg, 400 cGy of TBI with cyclosporine-A/mycophenolate mofetil and no ATG. Eligible patients for this analysis included first allograft recipients aged < 70 years with acute leukemia, MDS, MPD (all < 10% blasts pre-transplant), B-cell NHL or HL. Patients were scored by the rDRI (with FLT-3 positivity categorized as high risk) and aaHCT-CI. PFS was estimated using the Kaplan-Meier method, while Cox proportional hazards regression models were used to assess the association between patient and graft characteristics and PFS. Results: Patients [n = 100, median age 51 years (range 19-70) and median weight 78 kg (32-139) had AML (38 CR1,17 CR2, 1 refractory), ALL (13 CR1, 2 CR2, 1 CR3), MDS (10, blasts ranging 1-10%), MPD (5), B-cell NHL (11 DLBCL or indolent) or HL (2). The rDRI distribution was 6 (6%) low, 55 (55%) intermediate, 34 (34%) high, and 5 (5%) very high whereas the median aaHCT-CI was 3 (range 0-9). The median infused CD34+ cell doses of the larger and smaller units were 1.17 (range 0.35-3.72) and 0.68 (range 0.17-2.18) x 105/kg, respectively, whereas the median 8 allele HLA-match was 5/8 (range 2-8/8). In 42/100 (42%) patients the dCBT grafts were supplemented by CD34+ cell selected haplo-identical peripheral blood stem cells. The cumulative incidence of day 45 neutrophil engraftment was 97% whereas day 100 grade II-IV and III-IV aGVHD were 69% and 15%, respectively, and 1-year chronic GVHD was 6%. Day 180 TRM was 17% and 2-year relapse incidence was 11%. With a median survivor follow-up of 27 months (range 5-91), the 2-year PFS was 66% (95%CI: 56-75). Kaplan-Meier estimates and univariate and multivariate analyses of 2-year PFS by relevant patient and graft variables are shown (Table and Figures). Dividing patients into low-intermediate vs high-very-high rDRI and aaHCT-CI 0-2, 3 and > 4 revealed high aaHCT-CI was associated with worse PFS whereas older age alone and high-very high rDRI were not. The adverse effect of high aaHCT-CI was mediated by an increased risk of TRM early post-transplant. Conclusions: dCBT with intermediate intensity conditioning (Cy/Flu/Thio/TBI 400) is effective in adult patients with high-risk malignancies. Notably, pre-transplant rDRI was not associated with PFS suggesting this therapy is associated with a robust graft-versus-malignancy effect. High aaHCT-CI, however, adversely impacted PFS. These findings support the use of intermediate intensity dCBT in patients with high risk disease without concurrent high aaHCT-CI, and, as with adult donor allografts, new treatment strategies are required for patients with a significant co-morbidity burden. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Giralt: JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding. Scaradavou:National Cord Blood Program- New York Blood Center: Employment.

scholarly journals WT1 mRNA Expression in the Peripheral Blood of Patients with MDS Yields Additional Prognostic Information within the IPSS-R Risk Categories "Very Low", "Low" and "Intermediate"

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1827-1827
Author(s):  
Christina Rautenberg ◽  
Sabrina Pechtel ◽  
Norbert Gattermann ◽  
Rainer Haas ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Peripheral Blood ◽  
Research Funding ◽  
Risk Groups ◽  
Prognostic Information ◽  
Expression Status ◽  
Very High ◽  
Risk Categories ◽  
Who 2008

Abstract Introduction: The revised version of the International Prognostic Scoring System, (IPSS-R), is an accepted standard for assessing the prognosis of patients with MDS. Its usefulness may be further improved by integrating molecular findings. However, such efforts are impeded by limited access to molecular diagnostics, lack of standardized methodology, and a relatively low frequency of individual gene mutations in MDS. The Wilms' Tumor-1 (WT1) gene is overexpressed on mRNA level in the peripheral blood (PB) in about 50% of patients with MDS. The aim of this analysis was to determine whether PB WT1 expression status yields additional prognostic information. Methods: For this purpose, PB WT1 mRNA expression was measured in 91 newly diagnosed patients with MDS (WHO: MDS del5q, n=7; RARS, n=1; RCUD, n=4; RCMD, n=37; RAEB-I, n=16; RAEB-II, n=23; MDS/MPN unclassifiable, n=3 / IPSS-R: very low risk, n=3; low risk, n=28; intermediate risk, n=27; high risk, n=13; very high risk, n=20), using the Ipsogen® WT1 ProfileQuant® Kit. This standardized, commercially available assay uses a validated cut-off level of 50 WT1 copies/104ABL copies for discrimination between normal and overexpression of WT1 in PB. MDS patients in our study cohort were stratified accordingly (normal WT1 expression with <50 WT1 copies versus overexpression with >50 WT1 copies). WT1 expression status was correlated with clinical parameters and outcome. Results: Overall, 53 MDS patients (58%) showed WT1 overexpression, which correlated significantly with WHO 2008 disease category and IPSS-R risk groups, as indicated by both the absolute WT1 levels (correlation with WHO 2008 type, p=0.0028, and IPSS-R, p=0.0075) and the frequency of WT1-overexpressing patients within the respective MDS subgroup (correlation with WHO 2008 type, p=0.0029, and IPSS-R, p=0.0027). Regarding the entire cohort, patients with elevated WT1 expression had a significantly lower progression-free survival (PFS) and overall survival (OS) compared to those with normal WT1 expression (p<0.0001 and p=0.0306). Furthermore, within the IPSS-R risk groups 'very low', 'low' and 'intermediate', PFS differed significantly between patients showing normal vs. elevated WT1 expression status (IPSS-R very low/low: median PFS 30.1 months vs. not reached, for WT1 high vs normal, respectively, p=0.0127; IPSS-R intermediate: median PFS 14.4 months vs. 59.5 months, for WT1 high vs. normal, respectively p=0.0240). These differences in PFS retained their prognostic significance in multivariate analysis after adjusting for IPSS-R (HR 0.306; 95% CI 0,156-0,598, p=0.001). However, they did not translate into a difference in overall survival, which was probably due to a relevant number of patients proceeding to allogeneic stem cell transplantation. Given the large proportion of patients displaying WT1 overexpression in the IPSS-R high and very high risk groups, it was not surprising that no significant prognostic subdivision by WT1 expression level was seen in these risk categories. Conclusion: Our results show that PB WT1 expression offers additional prognostic information in patients belonging to the IPSS-R risk groups 'very low', 'low' and 'intermediate'. Assessment of WT1 expression status at diagnosis is a relatively time and cost efficient method that can be performed without patient discomfort and may help to identify MDS IPSS-R low and intermediate patients at risk for early progression. Disclosures Rautenberg: Celgene: Honoraria. Germing:Janssen: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kobbe:Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding. Schroeder:Celgene: Consultancy, Honoraria, Research Funding.

Impact of Refined Disease Risk Index after Single and Double Umbilical Cord Blood Transplantation in Adults with Hematological Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3484-3484
Author(s):  
Annalisa Paviglianiti ◽  
Annalisa Ruggeri ◽  
Guillermo Sanz ◽  
Noel Milpied ◽  
Didier Blaise ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Risk ◽  
Risk Index ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Large Cohort ◽  
Low Risk ◽  
Advisory Committees ◽  
Blood Transplantation ◽  
Very High

Abstract Identifying pre-transplant risk factor before allogeneic transplantation (HSCT) is important, regardless of the graft source. Nonetheless, it has been demonstrated that disease type and status at the time of HSCT significantly affect outcome. Disease risk index (DRI) has been recently defined for stratifying large and heterogeneous cohorts of patients (pts) undergoing HSCT. The original DRI included all hematological malignancies (except very rare diseases) and was able to define 4 distinct groups with different outcomes, dividing patients by disease type and status and considering cytogenetics that turned to be determinant for acute myeloid leukemia and myelodysplastic syndromes (MDS). Recently, DRI was refined by including rare diseases and improving MDS stratification by blast percentage, cytogenetics and response to prior therapy. DRI has been demonstrated to be applicable to pts undergoing HSCT regardless of age, conditioning regimen and graft source, and it has also been validated in pts undergoing T-cell depleted HSCT. Currently, there are no available reports on large cohort of pts undergoing umbilical cord blood transplantation (UCBT). Our aim was to determine the impact of DRI after UCBT. We retrospectively analyzed 2337 adults who underwent UCBT between 2004 and 2014, were reported to Eurocord and had available data for DRI scoring. Diagnosis was acute leukemia (AL) in 66% of the cases; 56% of AL were transplanted in first complete remission (CR), 39% in CR2 and 6% in >CR2. The median age at UCBT was 43 (range 18-76) years. Cytomegalovirus (CMV) serology was positive in 62% of pts; 45% of pts were female. Performance status at UCBT was <90% in 56% of pts and >90% in 44%. Fifty-two percent of pts received double and 48% single UCBT. Conditioning regimen was reduced intensity (RIC) for 52% of pts, and the most common regimen was cyclophosphamide+fludarabine+low dose total body irradiation (2Gy) for 72% of pts. Cyclosporine A (CsA) and mycophenolate mofetil (MMF) were used for graft-versus-host-disease (GVHD) prophylaxis in 61% of the pts. Anti-thymocyte globulin (ATG) was given in 41% of pts. Median TNC at cryopreservation was 4.2 x 107/Kg (range 0.4-13) and 56% of pts received a graft with 2or more HLA mismatches.The median follow-up was 30 (range 1-120) months. Overall survival (OS) and progression free survival (PFS) were 44% and 38% at 2 years, respectively. Refined DRI stratified pts in 4 subgroup (low risk, n=352, intermediate, n=1303, high, n=544, and very high-risk, n=138). OS was 56±3% for pts with low-risk DRI, 48±2% for intermediate-risk DRI, 31±2% for pts with high-risk DRI and 26±4% for pts with very high-risk DRI (p <0.0001). PFS was 46±3%, 42±2%, 25±2%, 22±4% for low, intermediate, high and very-high risk, respectively (p <0.0001). According toconditioning intensity regimen and DRI, OS was 49% (for low risk), 47% (for intermediate), 29% (for high risk) and 20% (for very high risk) (p< 0.0001) for myeloablative (MAC) regimen and 60% (for low risk), 49% (for intermediate), 33% (for high risk) and 32% (for very high risk) for RIC (p < 0.0001). DRI was also statistically associated with different PFS stratifying for type of conditioning regimen (MAC and RIC)(p <0.0001). In multivariate analysis adjusted for ATG use, CMV serology, DRI, median age at UCBT, median TNC at cryopreservation and type of UCBT (single or double), ATG use (HR=1.52, CI 95%=1.3-1.7, p< 0.0001), age at UCBT (median) (HR=1.4, CI 95%=1.2-1.6, p <0.001), very-high DRI (HR=2.7, CI 95%=2-3.7, p< 0.001), positive CMV serology (HR=1.2, CI 95%=1.07-1.4, p 0.03) were associated with a decreased OS. Furthermore, ATG use (HR=1.4, CI 95%=1.2-1.5, p< 0.0001), age at UCBT (median) (HR=1.3, CI 95%=1.2-1.5, p <0.0001), very-high DRI (HR=2.2, CI 95%=1.6-3, p< 0.0001), positive CMV serology (HR=1.2, CI 95%=1.04-1.4, p 0.008) were associated with decreased PFS. Refined DRI is a valid system for risk-stratifying pts with different diseases undergoing UCBT in retrospective large cohort studies. This index represents a simple and robust means of stratifying large cohort of pts in the UCBT setting, complementary to other existing pre-transplant index. Our results confirm the prognostic value of refined DRI in UCBT and support the use of this simple tool for prospective trials in the future. Disclosures Bloor: Janssen: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Gilead: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Validation and Refinement Of The Disease Risk Index For Stratification Of Patients Undergoing Allogeneic Stem Cell Transplantation: A Study Of 13,131 Patients From The Center For International Blood & Marrow Transplant Research

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 548-548
Author(s):  
Philippe Armand ◽  
Haesook T. Kim ◽  
Brent R. Logan ◽  
Zhiwei Wang ◽  
Edwin P. Alyea ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
High Risk ◽  
Hodgkin Lymphoma ◽  
Disease Risk ◽  
Early Stage ◽  
Risk Index ◽  
Low Risk ◽  
Advanced Stage ◽  
Very High

Abstract Disease type and status at the time of allogeneic hematopoietic stem cell transplantation (HSCT) dominantly influence HSCT outcome. It is therefore important to stratify patients by disease risk in any retrospective or prospective transplantation study that enrolls patients across multiple disease types or status. We previously proposed a Disease Risk Index for this purpose, based on a retrospective study of patients transplanted at 2 institutions (Armand et al, Blood 2012;120:905). Here we present the results of a study designed to validate and refine the DRI in a larger multicenter population. We included 13,131 adult patients who underwent HSCT for hematologic malignancies, excluding very rare diseases, between 2008 and 2010 and were reported to the CIBMTR. Their median age was 52 (range, 18-80) years. The cohort included a broad representation of diseases, disease status, donor types, and graft sources. 53% of patients were conditioned with a myeloablative regimen. The median follow-up for survivors was 24 months. The original DRI stratified patients into 4 groups with 2y OS of 64% in the low-risk, 51% in the intermediate, 34% in the high, and 24% in very high risk group (p<0.0001). DRI group was the most important prognostic factor in multivariable analysis, with a hazard ratio (HR) for mortality of 1.5, 2.3 and 3.0 for the intermediate, high and very high risk groups respectively compared to the low risk group (p<0.0001 for all). In addition, the DRI retained its discriminatory ability across all graft source, age, donor type, and conditioning intensity groups. The large cohort size also allowed us to examine each possible disease/status combination, which we used to refine the original DRI. We created 4 broad risk groups based on a multivariable model containing all possible such combinations, with cutoffs based on proportional increments in the hazard for mortality in comparison to AML with intermediate cytogenetics in 1stcomplete remission. Each broad group, except for the very high risk one, could be further divided into 2 subgroups with significantly different OS, yielding a 7-group index for use with larger cohorts. This revised DRI (Table and Figure) outperformed the original DRI and other existing stratification systems based on a calculation of the c-statistic. We propose that this revised DRI could be used for risk stratification in retrospective studies, in the analysis of clinical trial results, and in the adjustment of disease risk for the Stem Cell Therapeutic Outcomes Database. Table DISEASE and STAGE DRI Subgroup % pts 2yOS (95CI) DRI Group % pts 2yOS (95CI) Hodgkin Lymphoma, Indolent B-NHL, MCL or CLL, any CR Low-1 4% 74% (69-78) Low 14% 66% (63-68) Indolent B-NHL or CLL, PR Low-2 10% 62% (59-65) AML Favorable cyto ,any CR CML, Chronic Phase T-NHL, any CR Int-1 51% 52% (51-54) Int 62% 51% (50-52) ALL, 1st CR AML Intermediate cyto, any CR Myeloproliferative neoplasms, Any Stage Low-risk MDS, Any cyto, Early Stage* Multiple myeloma, CR/VGPR/PR Aggressive B-NHL, any CR Hodgkin lymphoma or MCL, PR Aggressive B-NHL or T-NHL, PR Int-2 11% 46% (43-49) Low-risk MDS Int cyto ,Advanced Stage or High-risk MDS Int cyto, Early Stage CML, Advanced Phase Indolent B-NHL or CLL, Advanced Stage* Aggressive NHL, PR High-risk MDS Int cyto, Advanced Stage* High-1 6% 39% (36-43) High 20% 33% (31-35) AML Favorable cyto, Advanced Stage* Burkitt lymphoma, CR AML Adverse cyto, CR ALL, 2nd CR High-risk MDS Adv cyto, Any Stage or Low-risk MDS Adv cyto Advanced Stage* High-2 14% 31% (28-33) Hodgkin Lymphoma, MCL or T-cell NHL, Advanced Stage* ALL, 3rd or higher CR Multiple myeloma, Advanced Stage* AML Intermediate cyto, Advanced Stage* CML, Blast Phase Very High 4% 23% (20-27) Very High 4% 23% (20-27) ALL, Advanced Stage* Aggressive NHL, Advanced Stage* AML Adv cyto, Advanced Stage* Burkitt lymphoma, PR or Advanced Stage* * Advanced stage is induction failure or active relapse, including stable or progressive disease for lymphoma and CLL; for MDS, early stage is untreated, CR, or improvement with therapy without CR. MCL, mantle cell lymphoma; cyto, cytogenetics (classified as in original DRI except that complex karyotype was defined as >3 abnormalities for both MDS and AML and t(8;21) was favorable for AML); int, intermediate; adv, adverse; pts, patients; OS, overall survival. Figure Overall Survival in the Entire Cohort, Stratified by revised DRI. A. DRI overall groups; B. DRI subgroups. Figure. Overall Survival in the Entire Cohort, Stratified by revised DRI. A. DRI overall groups; B. DRI subgroups. Disclosures: No relevant conflicts of interest to declare.

scholarly journals High Incidence of Venous Thromboembolism in Patients with Chronic Graft-Versus-Host Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-46
Author(s):  
Najla El Jurdi ◽  
Heba Elhusseini ◽  
Todd E. DeFor ◽  
Grigori Okoev ◽  
Aleksandr Lazaryan ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Advisory Committees ◽  
High Incidence ◽  
Independent Association ◽  
Very High ◽  
Fund Research

Background: Limited studies report a wide range of venous thromboembolism (VTE) incidence among allogeneic hematopoietic cell transplant (alloHCT) recipients. Chronic GVHD (cGVHD) is an immune mediated complication after alloHCT associated with vascular endothelial damage and prolonged systemic inflammation. We hypothesized that patients developing cGVHD are a subgroup at particularly high risk for VTE. Aims: To assess VTE incidence, sites of involvement, and risk factors in patients with cGVHD and to examine the impact of VTE on clinical outcomes after alloHCT. Methods: We performed a retrospective cohort study of all 145 patients who developed cGVHD after a matched sibling (MSD) and umbilical cord blood (UCB) donor alloHCT from 2010 to 2018. VTE was defined as a new confirmed event by imaging at any time after cGVHD diagnosis. VTE sites were categorized as upper extremity (UE), lower extremity (LE) deep vein thrombosis (DVT) or pulmonary embolus (PE). We assessed the cumulative incidence of VTE treating non-VTE mortality as a competing risk. Multivariate regression was used to evaluate the independent association of risk factors with the incidence of VTE using predefined factors in our model including gender, age, DRI, cGVHD severity, days to cGVHD from transplant and platelet level. We accounted for multiple events of VTE using PWP regression. Cox and Fine and Gray regressions were used to evaluate the independent association of time-dependent VTE on overall survival (OS) and non-relapse mortality (NRM), respectively using propensity scoring to control for confounding.. Results: Median age at time of cGVHD diagnosis was 52 years (range 19-74). 104 (72%) patients received MSD and 41 (28%) UCB alloHCT. Of the 145 patients with cGVHD, 32 (22%) developed either 1 or 2 VTE events and 14 (10%) developed 2 VTE events. The first VTE events were PE (n=6, 19%), and DVT (n=26, 81%; n=17 LE, n= 8 UE and n=5 catheter related UE DVT); one patient developed an IVC thrombus. The second VTE events were PE (n=2, 14%), and DVT (n=12, 86%; n=5 LE, n= 7 UE and n=4 catheter related UE DVT). Most patients were on corticosteroids at the first (n=28, 88%) and second (n=10, 71%) VTE with a median dose of (0.3 and 0.2 mg/kg/day, respectively) ± additional immunosuppression therapies. The cumulative incidence of VTE through 5 years post cGVHD diagnosis was estimated at 22% (95% CI: 15-29%) with median time from cGVHD diagnosis to VTE of 234 days (IQR 85-599). Median time to the development of LE DVT or PE was shorter than UE DVT (107 vs 450 days, respectively). Incidence was higher in males (24% vs 18%), and was not significantly different by age (&lt; or ≥50), BMI (&lt; or ≥30), HCT- comorbidity index, donor type, conditioning regimen and GVHD prophylaxis. Cumulative incidence was higher (50%) in patients with high/very high risk DRI compared to 19% in those with low and intermediate risk DRI. VTE incidence was highest in patients with de novo cGVHD (25%) compared to quiescent (20%) and progressive type (17%). Cumulative incidence was 9%, 17% and 38% in those with mild, moderate and severe GVHD respectively. Patients with lung, gastrointestinal, genitourinary and liver cGVHD had a higher incidence of VTE. Patients developing cGVHD &gt;6 months from HCT had a higher incidence of VTE (24% vs 19%). In multivariate analysis, high/very high risk DRI was associated with higher risk of VTE (HR 2.5; 95% CI; 1.2-5.3) (Figure 2). VTE was not associated with a significantly higher 2-year NRM (HR 1.2; 95% CI; 0.4-3.6) or 5 year OS (HR 1.4; 95% CI; 0.7-3.0). Conclusion: Patients who develop cGVHD after alloHCT have a high incidence VTE. Identifying a subgroup at a particularly high risk for VTE could inform thromboprophylaxis and other supportive care strategies for prevention of such events. Disclosures Bachanova: Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; FATE: Research Funding; BMS: Research Funding; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Betts:Patent Pending: Patents & Royalties: Dr. Betts has a pending patent WO2017058950A1: Methods of treating transplant rejection. This includes the use of JAK inhibitors. Neither he nor his institution have received payment related to claims described in the patent.. Blazar:Tmunity: Other: Co-founder; Magenta Therapeutics: Consultancy; KidsFirst Fund: Research Funding; Fate Therapeutics Inc.: Research Funding; Childrens' Cancer Research Fund: Research Funding; BlueRock Therapeuetic: Consultancy; BlueRock Therapeutics: Research Funding. Brunstein:Astex: Research Funding; AlloVir: Other: Advisory board; Magenta: Research Funding; Gamida: Research Funding. Holtan:CSL Behring: Other: Clinical trial data adjudication; BMS: Consultancy; Generon: Consultancy; Incyte: Consultancy. Janakiram:Takeda, Fate, Nektar: Research Funding. Gangaraju:Sanofi Genzyme, Consultant for Cold Agglutinin Disease: Consultancy. MacMillan:Talaris Therapeutics, Inc: Consultancy; Angiocrine Biosciences, Inc.: Consultancy; Equillium, Inc.: Consultancy; Fate Therapeutics, Inc.: Consultancy; Mesoblast: Consultancy. Rashidi:Synthetic Biologics: Other: DSMC member (1 trial) and related honorarium. Weisdorf:Incyte: Research Funding; FATE Therapeutics: Consultancy. Arora:Pharmacyclics: Research Funding; Fate Therapeutics: Consultancy; Kadmon: Research Funding; Syndax: Research Funding.

scholarly journals Myeloablative Conditioning Is Preferred for Allogeneic Transplantation of Acute Myeloid Leukemia and Myelodysplastic Syndromes with Low/Intermediate but Not High Disease Risk Index

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4603-4603
Author(s):  
Nelli Bejanyan ◽  
Mei-Jie Zhang ◽  
Khalid Bo-Subait ◽  
Hai-Lin Wang ◽  
Erica D. Warlick ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Disease Risk ◽  
Risk Index ◽  
Intermediate Risk ◽  
Myeloablative Conditioning ◽  
Conditioning Intensity ◽  
Very High ◽  
Risk Of Relapse

Although some data (Scott, JCO 2017) suggest that myeloablative conditioning (MAC) is preferred for allogeneic hematopoietic cell transplantation (HCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), these data were not informed by analysis of disease specific risk factors. We analyzed AML and MDS HCT outcomes stratified by the disease risk index (DRI) in order to identify the preferred transplant conditioning intensity (reduced-intensity conditioning [RIC] vs. MAC). In this large CIBMTR registry study we identified 4387 adult patients (age 40-65 years) who received HCT for AML (68%) or MDS (32%) between 2009 and 2015. DRI was stratified as low/ intermediate risk (1539 MAC and 999 RIC) and high/ very high risk (1121 MAC and 728 RIC). Examining the low/ intermediate risk DRI cohort (Table), RIC was associated with lower risk of TRM (HR=0.74, 95% CI 0.62-0.88; p<0.001) but significantly higher risk of relapse (HR=1.54, 95% CI 1.35-1.76; p<0.001). As a result, RFS in this cohort was significantly worse with RIC (HR=1.19, 95% CI 1.07-1.33; p=0.001). In the high/ very high risk DRI cohort, RIC resulted in similar TRM (HR=0.83, 95% CI 0.68-1.00; p=0.051) but again significantly higher risk of relapse (HR=1.23, 95% CI 1.08-1.41; p=0.002). RFS in high/ very high risk DRI cohort was similar between RIC and MAC. Adjusted outcome curves for the 3 endpoints are shown in the Figure. In this large study of HCT for AML or MDS stratified by DRI, RIC was independent predictor of lower TRM, but significantly higher risk of relapse. The MAC was an independent predictor of lower relapse in both low/ intermediate and high/very high DRI groups. However, MAC only resulted in RFS benefit in the low/ intermediate group where the magnitude of impact on relapse was not offset by the higher TRM. In adults with AML or MDS aged 40-65 years, these data support MAC as the preferred conditioning intensity for low/ intermediate risk DRI, whereas MAC does not provide significant benefit in those with high/ very high risk DRI. Safer, yet still potent MAC regimens could benefit this higher risk group. Disclosures Bejanyan: Kiadis Pharma: Other: advisory board. Brunstein:Gamida: Research Funding; Astex: Research Funding; Magenta: Research Funding. Kebriaei:Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria; Pfizer: Honoraria; Kite: Honoraria. Weisdorf:Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy; Incyte: Research Funding.

scholarly journals p53 Mutant Independently Impacts Risk: Analysis of Deletion 5q, Lower-Risk Myelodysplastic Syndromes (MDS) Patients Treated with Lenalidomide (LEN) in the MDS-004 Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 414-414 ◽  
Author(s):  
Leonie Saft ◽  
Jack Shiansong Li ◽  
Peter L. Greenberg ◽  
Mikkael A. Sekeres ◽  
Guillermo F. Sanz ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Lower Risk ◽  
Research Funding ◽  
Risk Group ◽  
Risk Groups ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Very High

Abstract Introduction: Refined risk-classification of patients (pts) with MDS allows for improved treatment selection for individual pts. The Revised International Prognostic Scoring System (IPSS-R) has recently been validated as a prognostic tool in lower-risk MDS pts with deletion 5q [del(5q)], who were treated with LEN in the MDS-004 study (Sekeres et al. Blood Cancer J 2014; in press). P53 nuclear protein expression, as assessed by immunohistochemistry (IHC), predicted overall survival (OS) and risk of progression to acute myeloid leukemia (AML) in lower-risk MDS pts with del(5q) (Saft et al. Haematologica 2014;99:1041-9). This analysis evaluated the prognostic value of adding p53 IHC to IPSS-R to predict OS and AML progression in pts with lower-risk MDS with del(5q). Methods: In a subset of 85 pts from MDS-004 with bone marrow (BM) biopsies available, p53+ staining (≥ 1% IHC+++ BM cells) was visualized by IHC. Twenty-four pts had missing IPSS-R scores; 1 due to lack of baseline cytogenetic data and 23 because of missing exact BM blast percentage. Thus, 61 pts (42 initially treated with LEN and 19 with placebo) had IPSS-R and p53 IHC data available; 89% of pts in the placebo group crossed over to LEN 5 mg at Week 16. The IPSS-R Very Low and Very High risk groups with < 5 pts were combined with the Low and High risk groups, respectively. AML-free survival (AFS), OS, and time to AML progression within p53 IHC status (p53+ vs p53−), and IPSS-R risk groups were characterized by the Kaplan-Meier method with differences evaluated by the log-rank test. Results: Of 61 pts, 38% were p53+. There was a linear increasing trend in the proportion of pts with p53+ across IPSS-R risk groups from Very Low/Low, Intermediate to High/Very High (29%, 47% and 63%, respectively; Cochran-Armitage trend test P = 0.050). The 3 IPSS-R risk groups significantly predicted AFS and OS (log-rank P < 0.001 for both AFS and OS), but not time to AML progression (P = 0.335). Overall, AFS, OS, and time to AML progression differed significantly between p53+ versus p53− pts (23.9 vs 47.9 months for median AFS, P = 0.003; 27.0 vs 50.6 months for median OS, P = 0.005; and 44.3 months vs not reached [NR] for median time to AML progression,P = 0.003). In the IPSS-R Very Low/Low risk group (n = 38), AFS, OS, and time to AML progression were significantly worse in p53+ versus p53− pts (20.1 vs 63.1 months for median AFS, P = 0.011; 28.4 vs 76.8 months for median OS, P = 0.031; and 65.2 months vs NR for median time to AML progression, P = 0.014). Results for all IPSS-R risk groups in pts with p53 and IPSS-R data are presented in the Figure. The lack of significant differences between p53+ versus p53− pts in the Intermediate and High/Very High risk groups is likely due to the small sample size of these groups. Conclusions: In this exploratory subset analysis of lower-risk MDS pts with del(5q), p53 IHC status in the IPSS-R Very Low/Low risk group significantly impacted AFS, OS, and AML progression. These data support the addition of p53 mutational analysis to prognostic risk assessment which should help inform the selection of appropriate treatment for individual MDS pts with del(5q). These results need to be validated in a large sample set, which will be accomplished as part of the ongoing efforts to include prognostic molecular mutations in future updates of IPSS-R Figure 1 AFS (A), OS (B), and time to AML progression (C) in pts with p53 and IPSS-R data (N = 61) Figure 1. AFS (A), OS (B), and time to AML progression (C) in pts with p53 and IPSS-R data (N = 61) Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Shiansong Li: Celgene Corporation: Employment, Equity Ownership. Greenberg:Celgene: Research Funding; Onconova: Research Funding; GSK: Research Funding; Novartis: Research Funding; KaloBios: Research Funding. Sekeres:Amgen Corp.: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corp.: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Dreyfus:Novartis: Honoraria; Celgene: Honoraria. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding. Swern:Celgene: Employment, Equity Ownership. Sugrue:Celgene: Employment, Equity Ownership. Hellstrom-Lindberg:Celgene: Research Funding.

scholarly journals Clinical Significance of Risk Stratification Based on Disease Risk Index and Hematopoietic Cell Transplantation-Comorbidity Index

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2539-2539
Author(s):  
Takayuki Sato ◽  
Shinichi Ochi ◽  
Takashi Nagayama ◽  
Shogo Nabe ◽  
Kazuya Sakai ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Cumulative Incidence ◽  
Hematopoietic Cell Transplantation ◽  
Disease Risk ◽  
Risk Index ◽  
Performance Status ◽  
Allogeneic Hct ◽  
Group I ◽  
Very High

Abstract Introduction: Allogeneic hematopoietic cell transplantation (HCT) has curative potential for a variety of hematologic malignancies. However, the success of HCT is heavily dependent on the disease and remission status. Armand et al. recently proposed a disease risk index (DRI) to assess the risk for allogeneic HCT based on the disease and remission status, and could be used to risk stratification on survival (Armand et al Blood 2012), but evaluation of its clinical significance is limited. HCT-comorbidity index (HCT-CI) was developed as a measure of pretransplant organ dysfunctions (Sorror et al Blood 2005), which has been shown to be associated with nonrelapse mortality (NRM). In order to clarify any association between pretransplant factors including DRI and HCT-CI, and respective overall survival (OS), NRM and relapse rate, we retrospectively reviewed the data of patients who underwent allogeneic HCT at our department. Patients and Methods: A total of 305 patients with hematologic malignancies who underwent initial allogeneic HCT at our department between January 2000 and April 2013 were included. After excluding patients with insufficient HCT data, we included a total of 244 patients (138 male, 106 female) with a median age of 49.5 (range 15-69) years. A total of 133 patients received myeloablative conditioning and 111 received reduced-intensity regimens. Stem cell sources were bone marrow (n=177), peripheral blood (n=32), combined peripheral blood and bone marrow (n=1), and cord blood (n=34). A total of 146 patients received tacrolimus-based regimens and 98 patients received cyclosporine-based regimens for GVHD prophylaxis. The DRI has four risk-based categories (low, intermediate, high, and very high) and the HCT-CI has three categories in order of ascending risk (0, 1-2 and ≥3). OS was calculated with the Kaplan-Meier method, compared among groups with the log-rank test, and multivariable Cox regression analyses were used to evaluate factors associated with OS. The cumulative incidence of NRM and relapse were calculated while treating relapse and death without relapse, respectively, as competing events, and competing risk regression analyses were used to evaluate risk factors associated with NRM and relapse. Results: The median follow-up for survivors was 4.7 years (range 0.1-14.2 years). Pretransplant disease risks in the DRI low, intermediate, high, and very high risk groups were 8%, 60%, 25%, and 7%, and 4-year OS in the same groups were 74%, 64%, 35%, and 12%, respectively (Figure 1, p<0.001). Four-year OS among patients with a HCT-CI of 0, 1-2, and ≥3 were 63%, 52%, and 41%, respectively. Multivariable analysis showed a significant association with OS for DRI (high risk hazard ratio [HR] 2.62, p<0.001; very high risk HR 5.26, p<0.001 versus intermediate risk), HCT-CI (HCT-CI ≥3 HR 1.64, p=0.022 versus HCT-CI 0-2), 2-4 performance status (HR 3.10, p<0.001), and donor-recipient ABO minor-mismatch (HR 2.00, p=0.005 versus ABO match). The cumulative incidence of 4-year NRM was 25%, and NRM was significantly associated with HCT-CI (HCT-CI ≥3 HR 2.27, p=0.003 versus HCT-CI 0-2) and 2-4 performance status (HR 3.89, p<0.001). The cumulative incidence of 4-year relapse was 25%, and relapse was significantly associated with DRI (high risk HR 2.26, p=0.012; very high risk HR 8.11, p<0.001 versus intermediate risk). Finally, we reclassified all patients into four risk groups incorporating DRI and HCT-CI: DRI low-intermediate plus HCT-CI 0-2 (group I), DRI low-intermediate plus HCT-CI ≥3, or DRI high plus HCT-CI 0-2 (group II), DRI high plus HCT-CI ≥3 (group III), and DRI very high (group IV). Four-year OS among patients with group I, II, III, and IV were 68%, 47%, 25%, and 12%, respectively (Figure 2, p<0.001). Conclusions: Our results suggest that risk stratification with DRI and HCT-CI for the prognosis of relapse and NRM may be useful for patients undergoing allogeneic HCT. Larger and prospective studies are warranted to more precisely validate these findings. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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