A disease risk index for patients undergoing allogeneic stem cell transplantation

Abstract The outcome of allogeneic HSCT varies considerably by the disease and remission status at the time of transplantation. Any retrospective or prospective HSCT study that enrolls patients across disease types must account for this heterogeneity; yet, current methods are neither standardized nor validated. We conducted a retrospective study of 1539 patients who underwent transplantation at Dana-Farber Cancer Institute/Brigham and Women's Hospital from 2000 to 2009. Using multivariable models for overall survival, we created a disease risk index. This tool uses readily available information about disease and disease status to categorize patients into 4 risk groups with significantly different overall survival and progression-free survival on the basis of primarily differences in the relapse risk. This scheme applies regardless of conditioning intensity, is independent of comorbidity index, and was validated in an independent cohort of 672 patients from the Fred Hutchinson Cancer Research Center. This simple and validated scheme could be used to risk-stratify patients in both retrospective and prospective HSCT studies, to calibrate HSCT outcomes across studies and centers, and to promote the design of HSCT clinical trials that enroll patients across diseases and disease states, increasing our ability to study nondisease-specific outcomes in HSCT.

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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 ◽

10.1182/blood.v128.22.988.988 ◽

2016 ◽

Vol 128 (22) ◽

pp. 988-988 ◽

Cited By ~ 1

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.

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A validated pediatric disease risk index for allogeneic hematopoietic cell transplantation

Blood ◽

10.1182/blood.2020009342 ◽

2020 ◽

Author(s):

Muna Qayed ◽

Kwang Woo Ahn ◽

Carrie L Kitko ◽

Mariam H Johnson ◽

Nirali N Shah ◽

...

Keyword(s):

Disease Risk ◽

Residual Disease ◽

Risk Index ◽

Disease Status ◽

Risk Groups ◽

Hematopoietic Cell ◽

Cell Transplant ◽

Hematopoietic Cell Transplant ◽

Free Survival ◽

Minimal Residual

A disease risk index (DRI) that was developed for adults with hematologic malignancy undergoing hematopoietic cell transplant is also being used to stratify children and adolescents by disease risk. Therefore, in this study, we analyzed 2569 patients aged <18 years with acute myeloid (AML; n=1224) or lymphoblastic (ALL; n=1345) leukemia undergoing hematopoietic cell transplant to develop and validate a DRI that may be used to stratify those with AML and ALL by their disease risk. Training and validation subsets for each disease were generated randomly with 1:1 assignment to the subsets and separate prognostic models were derived for each disease. For AML, four risk groups were identified based on age, cytogenetic risk, and disease status including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2, 3, 5), high (7, 8), and very high (>8) risk groups were 78%, 53%, 40%, and 25%, respectively, p<0.0001. For ALL, three risk groups were identified based on age and disease status including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2-4), and high (≥5) risk groups were 68%, 51%, and 33%, respectively, p<0.0001. We confirmed the risk groups can be applied for overall survival with 5-year survival ranged from 80% to 33% and 73% to 42% for AML and ALL, respectively (p<0.0001). This validated pediatric DRI that includes age and residual disease status can be used to facilitate prognostication and stratification of children with AML and ALL for allogeneic transplantation.

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Predictive value of disease risk comorbidity index for overall survival after allogeneic hematopoietic transplantation

Blood Advances ◽

10.1182/bloodadvances.2018018549 ◽

2019 ◽

Vol 3 (3) ◽

pp. 230-236 ◽

Cited By ~ 6

Author(s):

Nelli Bejanyan ◽

Claudio G. Brunstein ◽

Qing Cao ◽

Aleksandr Lazaryan ◽

Celalettin Ustun ◽

...

Keyword(s):

Overall Survival ◽

Scoring System ◽

Hematological Malignancies ◽

Clinical Decision Making ◽

Disease Risk ◽

Risk Index ◽

Assessment Tools ◽

Free Survival ◽

Comorbidity Index ◽

Disease Free

Abstract Allogeneic hematologic cell transplantation (alloHCT) is the only curative therapy for many adults with hematological malignancies. However, it can be associated with substantial risks of morbidity and mortality that are dependent on patient comorbidity– or disease risk–related factors. Several pretransplantation prognostic scoring systems have been developed to estimate survival of patients undergoing alloHCT; however, there is significant interstudy variability in the predictive capacity of these assessment tools. We tested the prognostic capability of a composite scoring system including the disease risk index and HCT comorbidity index (DRCI). The DRCI scoring system was applied pretransplantation to determine whether it predicted clinical outcomes of 959 adult patients with hematological malignancies undergoing alloHCT from 2000 to 2013 at the University of Minnesota. The DRCI score categorized patients into 6 risk groups, with 2-year overall survival ranging between 74% for the very low-risk DRCI group and 34% for the very high-risk DRCI group. In multiple regression analyses adjusted for patient age and donor type, the risk of overall mortality independently increased as the DRCI score increased. Additionally, the DRCI score independently predicted risk of relapse, disease-free survival, and graft-versus-host disease–free/relapse–free survival. Our data demonstrate that the pretransplantation DRCI scoring system predicts outcomes after alloHCT and can be used to guide clinical decision making for patients considering alloHCT.

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Comparable Outcomes for Hematologic Malignancies after HLA-Haploidentical Transplantation with Posttransplantation Cyclophosphamide and HLA-Matched Transplantation

Advances in Hematology ◽

10.1155/2015/431923 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 13

Author(s):

Shannon R. McCurdy ◽

Ephraim J. Fuchs

Keyword(s):

Overall Survival ◽

Disease Risk ◽

Risk Index ◽

Chronic Gvhd ◽

Progression Free Survival ◽

Hematologic Malignancies ◽

High Dose ◽

Safe Alternative ◽

Historical Cohort ◽

Clinical Scenarios

The implementation of high-dose posttransplantation cyclophosphamide (PTCy) has made HLA-haploidentical (haplo) blood or marrow transplantation (BMT) a cost effective and safe alternative donor transplantation technique, resulting in its increasing utilization over the last decade. We review the available retrospective comparisons of haplo BMT with PTCy and HLA-matched BMT in adults with hematologic malignancies. The examined studies demonstrate no difference between haplo BMT with PTCy and HLA-matched BMT with regard to acute graft-versus-host disease (aGVHD), nonrelapse mortality, and overall survival. Chronic GVHD occurred less frequently after haplo BMT with PTCy compared with HLA-matched BMT utilizing standard GVHD prophylaxis. In addition, patients with a high risk of relapse by the disease risk index had a suggestion of improved progression-free and overall survival after haplo BMT with PTCy when compared with a historical cohort of HLA-matched BMT in one analysis. Furthermore, in Hodgkin lymphoma relapse and progression-free survival were improved in the haplo BMT with PTCy compared with the HLA-matched BMT cohort. These findings support the use of this transplantation platform when HLA-matched related donors (MRDs) are unavailable and suggest that clinical scenarios exist in which haplo BMT may be preferred to HLA-matched BMT, which warrant further investigation.

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Haploidentical Transplant with Peripheral Blood Hematopoietic Cell Grafts in Older Adults with AML or MDS

Blood ◽

10.1182/blood.v128.22.4658.4658 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4658-4658

Author(s):

Michael Slade ◽

John F DiPersio ◽

Peter Westervelt ◽

Ravi Vij ◽

Geoffrey L. Uy ◽

...

Keyword(s):

Older Adults ◽

Overall Survival ◽

Cumulative Incidence ◽

Older Patients ◽

Research Funding ◽

Disease Risk ◽

Risk Index ◽

Hematopoietic Cell ◽

Comorbidity Index

Background: Modern post-transplant cyclophosphamide (PTCy) protocols with haploidentical (haplo) donors have dramatically expanded the donor pool for patients requiring hematopoietic cell transplantation (HCT). Initial studies were performed with bone marrow grafts, which require the donor to undergo anesthesia during harvest. Consequently, the use of mobilized peripheral blood hematopoietic cells (PBHC) may be desirable, especially with older donors. However, data on PBHC haplo-HCT in older adults is lacking. Objectives: To report the impact of age on transplant-related outcomes in a large cohort of patients undergoing haplo-HCT with PTCy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Methods: We retrospectively identified all adult patients undergoing T cell replete haplo-HCT with PTCy for AML or MDS at our institution from January 2009 to June 2016. Patients were grouped into three cohorts: Age1 (<55), Age2 (55-65) and Age3 (>65). Patients were scored for disease risk and underlying comorbidities using the Disease Risk Index (DRI) and HCT Comorbidity Index (HCT-CI). Overall survival (OS) was analyzed using a Cox Proportional Hazards (CPH) model, with all variables pre-specified. Results: We identified 107 patients, 92 with AML and 15 with MDS. Median follow up was 8.0 months in all patients and 18.3 months in patients surviving at last follow-up. Median donor age was 39, 34 and 49 in Age1, Age2 and Age3, respectively (p = 0.02). Donor relationship was also significantly different among Age1 (child: 25%, sibling: 53%, parent, 22%), Age2 (62%, 38%, 0%) and Age3 (64%, 36%, 0%) (p < 0.001). Younger patients were significantly more likely to receive myeloablative conditioning (55% vs. 35% vs. 27%, p = 0.04). Median OS was 448, 417 and 147 days in Age1, Age2 and Age3 patients. Actuarial 2-year OS was 40%, 34% and 11%, respectively. The 2-year cumulative incidence of relapse was 34%, 30% and 56%. The 2-year cumulative incidence of treatment-related mortality was 30%, 45% and 35%. There was a trend towards a lower 100-day cumulative incidence grade II-IV acute graft-versus host-disease (aGVHD) in older patients (44% vs. 35% vs. 15%, p = 0.07) but not in grade III-IV aGVHD (16% vs. 7% vs. 5%, p = 0.42). Similarly, there was a trend towards a lower 1-year cumulative incidence of cGVHD in older patients (37% vs. 36% vs. 10%, p = 0.07), but not severe cGVHD (5% vs. 0% vs. 0%, p = 0.16). No significant difference was seen in median time to neutrophil engraftment (17 vs. 18 vs. 17 days, p = 0.14) or platelet engraftment (28 vs. 30.5 vs. 32 days, p = 0.93). Univariate and multivariate CPH model of OS is summarized in table 1. Age > 65 and prior allogeneic HCT were associated with significantly worse survival. Conclusions: The use of PBHC haplo-HCT in older adults with AML or MDS is a feasible treatment option. However, a careful pre-transplant evaluation and analysis of risks and benefits is warranted when offering this transplant modality to older adults. Even after adjusting for pre-transplant comorbidity and disease risk, older age is associated with inferior survival in this cohort. Cox Proportional Hazard Analysis of Overall Survival. Abbreviations: Hematopoietic Cell Transplant Comorbidity Index (HCT-CI), Disease Risk Index (DRI) Figure 1 Overall survival by age Figure 1. Overall survival by age Disclosures DiPersio: Incyte Corporation: Research Funding. Vij:Takeda: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria. Schroeder:Incyte Corporation: Honoraria, Research Funding.

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Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplantation Cyclophosphamide in Primary Refractory Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.4411.4411 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4411-4411

Author(s):

Sarita Rani Jaiswal ◽

Sumita Chatterjee ◽

Aditi Chakrabarti ◽

Sneh Bhargava ◽

Ray Kunal ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Peripheral Blood ◽

Peripheral Blood Stem Cell ◽

Chronic Gvhd ◽

Progression Free Survival ◽

Disease Status ◽

Blood Stem Cell ◽

Post Transplantation ◽

Free Survival

Abstract In a pilot study, 75 patients with Primary Refractory (PRef) AML without matched family donors were offered post-transplantation cyclophosphamide (PTCY) based haploidentical peripheral blood stem cell (PBSC) transplantation. Twenty-seven patients (36%) opted for haploidentical transplantation with or without further chemotherapy. There was no difference in the patient or disease characteristics amongst patients undergoing transplantation or not. The conditioning regimen comprised of FluCyMel (n=5), FluBuMel (n=17) and FluTreoTBI (n=5). MMF was tapered between days 14 and 21 posttransplant in the absence of GVHD and cyclosporine A was tapered between days 60 and 90. The progression free survival at a median follow-up of 25 months was 36.6% and 0% in the transplant and the non-transplant group (p=0.0001). Prompt engraftment was noted at a median of 14 days irrespective of disease status or conditioning regimens. Cumulative incidences of acute graft-versus-host disease (GVHD) and chronic GVHD were 26.6% and 8% respectively. The overall incidence of infections remained low, with CMV reactivation and invasive aspergillosis occurring in 9 and 2 patients respectively. CMV disease was diagnosed in 2 patients. Non-relapse mortality at 1 year was 16.7%. The incidence of disease progression was 54%. Factors positively impacting progression free survival were < 15% marrow blasts at transplant and a Natural Killer Cell Ligand Mismatch (NKLMM) donor. NKLMM, Haplotype or B scores had no impact on CMV infection or GVHD. However, Bx Haplotype was associated with lower NRM (5%, 95%CI-1-9) compared to 48.6% (95%CI 28.2-69.0) in AA Haplotype (p=0.01). Disease status did not impact the overall survival (p=0.11) in the HSCT cohort. In fact, NKLMM donors with B haplotype had the greatest impact on overall survival in both the HSCT cohort (71.4%, 95%CI 54.3-88.5%) compared to 20% (95%CI 8.8-31.2, p=0.01) in those without the same. Our data suggests PTCY based Haploidentical PBSC transplantation is feasible in patients with PRef AML and donor NKLMM might improve progression free survival, provided the conditioning protocol and the post-grafting therapy offer the optimum platform for alloreactivity of NK cells. Disclosures No relevant conflicts of interest to declare.

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Refined Disease Risk Index (DRI) and Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) Predict Survival after Haploidentical Stem Cell Transplantation: A Comparative Study with EBMT Risk Score in 220 Consecutive Patients

Blood ◽

10.1182/blood.v126.23.4400.4400 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4400-4400 ◽

Cited By ~ 1

Author(s):

Maria Teresa Lupo-Stanghellini ◽

Elisa Sala ◽

Simona Piemontese ◽

Mara Morelli ◽

Raffaella Greco ◽

...

Keyword(s):

Risk Assessment ◽

Stem Cell ◽

Cell Transplantation ◽

Risk Score ◽

Hematopoietic Cell Transplantation ◽

Disease Risk ◽

Risk Index ◽

Hematopoietic Cell ◽

Comorbidity Index ◽

Very High

Abstract Background Optimization of pre-transplant risk assessment is a crucial issue to improve the allo-HSCT decision making process. Actually 3 major algorithms are in use in clinical practice: the EBMT risk score, the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score and - more recently introduced - the refined Disease Risk Index (DRI). DRI was defined to calibrate HSCT outcome across studies and centers. It was developed as a tool to assign patients into risk groups based on disease type and status at the time of transplantation. The aim of the DRI is to provide a robust tool that can be used for prognostication, for the analysis and interpretation of retrospective data, whether conducted in single-center, multicenter, or registry settings, or within the context of the federally mandated center outcome reporting. The DRI can also be used for the stratification of patients entering prospective HCT clinical trials. DRI is not a fixed tool but instead it was conceived to be refined by the transplant community as new information becomes available. Here we are presenting the results of a retrospective study designed to evaluate the 3 aforementioned score in stratification and prognostication of transplant outcome after a haploidentical HSCT (haplo-HSCT). Patients and Methods We included 220 adult patients (pts - 138 male, 82 female) who underwent a haplo-HSCT for hematologic malignancies, between 2006 and 2014 and were reported to our Institutional database. Risk assessment score and outcome analysis included all consecutive pts receiving an haplo-HSCT as 1st allogeneic transplantation. Pts receiving haplo-HSCT as 2nd or 3rd HSCT were excluded from the present analysis. Median age was 49 years (range, 15-77). The cohort included a broad representation of diseases (138/220 acute leukemia, 30 Hodgkin lymphoma); 62 pts were in complete remission at transplant, 158 were presenting active disease. Conditioning regimens mostly rely upon the combination of treosulfan plus fludarabine (201/220) and total body irradiation (range 200 - 400 cGy) was utilized in 52 patients. GVHD prophylaxis consisted mostly of an mTor inhibitor (rapamycin) combined with mycophenolate mofetil. The majority of patients received peripheral blood stem cells from a family haploidentical donor as stem cell source, while only 4 patients received bone marrow transplant. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki. Results The median follow-up for survivors was 37 months (r 6-107). The overall survival (OS) at 2-y was 35% and the transplant related mortality at 100-days 23%. The 2y OS according to EBMT / HCT-CI / DRI risk score are reported in table 1.a and figure 1. The evaluation of the HCT-CI impact after DRI stratification was able to show a significant difference in outcome showing better survival for pts with low DRI score and low HCT-CI score as expected (table 1.b). Discussion Refined DRI score and HCT-CI score predict survival after haplo-HSCT. The integrated application of refined DRI and HCT-CI may improve the definition of transplant eligibility for pts candidate to allogeneic HSCT form alternative donors including family haploidentical source. Table 1a. EBMT score 0-3 % pts 4-5 %pts > 5 %pts p 51% 17 34% 51 27% 32 0.07 HCT-CI score 0-2 3-4 >/= 5 48% 59 36% 31 0% 10 0.0001 DRI score Low-Intermediate High Very-High 61% 32 27% 51 5% 17 0.0001 Table 1b. HCT-CI 0-4 HCT-CI >/=5 p DRILow-Intermediate 64% 0% 0.0001 DRIHigh-Very High 29% 0% Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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Validation of a Modified Comorbidity Index for Allogeneic Hematopoietic Cell Transplant

Blood ◽

10.1182/blood.v128.22.1167.1167 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1167-1167 ◽

Cited By ~ 1

Author(s):

Todd E. DeFor ◽

Chap Le ◽

Angela R Smith ◽

Erica D. Warlick ◽

Nelli Bejanyan ◽

...

Keyword(s):

Regression Analysis ◽

High Risk ◽

Predictive Power ◽

Disease Risk ◽

Risk Index ◽

Cell Transplant ◽

Training Set ◽

Hematopoietic Cell Transplant ◽

Test Set ◽

Comorbidity Index

Abstract INTRODUCTION Among adult allogeneic hematopoietic cell transplant (HCT) recipients, the HCT-specific comorbidity index (HCT-CI) is a standard measure of baseline comorbidity. This measure incorporates 17 different comorbidities into a combined, categorically weighted score of standard, intermediate and high risk. Using the specific weights for each comorbidity from the single center analysis, the HCT-CI has been validated in other studies, most notably in a recent analysis including 8115 HCT recipients from the United States. The HCT-CI has been useful in controlling for confounding of comorbidities among patients. We previously reported that the efficiency and predictive power could be improved by removing the conversion of adjusted hazard ratios (HR) for non-relapse mortality (NRM) to three possible weights (1-3) for each comorbidity. METHODS Because some comorbidities show effects on a continuous scale and others show no effect, we proposed a weighting scheme in which each comorbidity is assigned the natural weight based on Fine and Gray regression analysis on NRM. The final modified comorbidity index (MCI) is based on a multiplicative model controlling for age, disease risk index, donor type and stratified by conditioning intensity. In this current study, we tested validation of calculations for the MCI by randomizing 2/3 of 1114 adult allogeneic patients with prospectively collected (2000-2015) comorbidities to a training set and 1/3 of patients to a test set. Using weights from the training set, we compared the MCI to the HCT-CI for the endpoints of NRM and overall survival (OS) in the test set. We did this using regression analysis and bootstrapping the difference in C-statistics for each method. RESULTS The median patient age was 51 (IQR: 39-59), 59% were male, donors included 41% HLA-matched sibling donors, 7% matched unrelated donors (URD) and 52% umbilical cord blood (UCB). Patients had malignant diagnoses with a disease risk index (DRI) of 19% low, 62% intermediate and 19% high or very high. Conditioning intensity included 65% reduced intensity (RIC) regimens. Using the HCT-CI, 19% were classified as low, 31% as intermediate and 39% as high risk. Based on the MCI, 34% were classified as low, 54% as intermediate and 12% as high risk. After adjusting for other factors, the independent weights for each comorbidity were calculated in our training set. We calculated the MCI by exponentiating the sum of all parameter coefficients from the regression analysis. The revised index score is: MCI = exponent [0.40*(binary indicator for cardiac disorders) + 0.85*(heart valve disease) + 0.05*(inflammatory bowel disease) + 0.48*(peptic ulcer) + 0.46* (diabetes) + 0.03*(psychiatric disturbance) + 0.20*(mild hepatic function) + 0.93*(moderate/severe hepatic function) + 0.19*(infection) + 2.00*(renal insufficiency) + 0.17*(moderate pulmonary abnormalities) + 0.39*(severe pulmonary abnormalities) + 0.16*(prior solid tumor)]. Comorbidities including obesity, cerebrovascular disease and rheumatologic disorders had no influence on NRM. This on-line calculator facilitates scoring of the modified index--MCI: http://bmt.ahc.umn.edu:8082/hct. In the test set (N=372), MCI was more predictive of NRM (table, fig 1a and 1b) and showed a trend toward increased sensitivity for OS compared to the original HCT-CI. The HR for intermediate and high risk categories increased (≥60% for NRM and >30% for OS). The adjusted likelihood ratio (showing model fit) increased from 20.3 to 22.5 for NRM and from 38.9 to 40.7 for OS when substituting MCI for HCT-CI. An increase shows better prediction of the endpoint. The C-statistic reflecting more NRM with a higher score and worse survival increased from 0.540 to 0.562 for NRM (P=0.02) and increased from 0.567 to 0.594 for OS (P=0.08). DISCUSSION This new MCI showed higher discriminating and predictive power for post-HCT NRM and a trend towards more predictive power for OS. As many HCT recipients have pre-existing comorbidities, the greater discrimination in assigning patient comorbidity will better inform decision-making for HCT recipients and HCT studies by better adjustment of these important risk factors. This MCI methodology should be used to create more efficient and predictive assessments in a larger multi-center study. Disclosures No relevant conflicts of interest to declare.

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Effect of Timing and Duration of Maintenance Lenalidomide in Myeloma Patients after Autologous Stem Cell Transplantations

Blood ◽

10.1182/blood.v124.21.194.194 ◽

2014 ◽

Vol 124 (21) ◽

pp. 194-194

Author(s):

Idrees Mian ◽

Denai Milton ◽

Uday R. Popat ◽

Nina Shah ◽

Yago Nieto ◽

...

Keyword(s):

Overall Survival ◽

Maintenance Therapy ◽

Research Funding ◽

Maintenance Treatment ◽

Progression Free Survival ◽

Disease Status ◽

Hazard Ratio ◽

P Value ◽

Free Survival ◽

Late Initiation

Abstract Introduction: Maintenance lenalidomide after autologous hematopoietic stem cell transplantation (auto HCT) has been shown to improve progression free (PFS) and overall survival (OS) in myeloma patients. In this analysis we sought to determine the impact of lenalidomide treatment on achievement of complete remission (CR), survival and the incidence of secondary primary malignancies (SPM). Methods: We retrospectively analyzed all (N=466) consecutive myeloma patients who underwent auto HCT and received maintenance lenalidomide between August 2006 and September 2013 at our institution. Patients received doses of maintenance lenalidomide ranging from 5 mg – 15 mg/day or every other day. We looked at whether lenalidomide improved disease status, specifically CR in patients who had not achieved this before maintenance initiation and the median time to achieve CR. We also analyzed the effects of early initiation (<4-months after auto HCT) of maintenance lenalidomide versus late initiation (≥ 4-months after auto HCT) with regards to PFS and OS using the Kaplan-Meier method. Lastly we assessed if continuation of maintenance therapy beyond 2 and 3-years after auto HCT improved PFS and OS and increased the incidence of SPM. Results: The median follow-up time for all patients was 26.6 months. 173 patients (37%) experienced improvements in their disease status. Of these, 86 patients (50% of those with noted improvements and 19% of total patients assessed) who were not in CR before maintenance achieved CR while on maintenance. The average time to achieve CR in these patients was 12.9 months. Comparing the patients who were started on early maintenance treatment with those who were started on late maintenance therapy, we did not find any difference with regards to PFS (Hazard Ratio [HR]=0.90; p-value=0.57) and OS (HR=0.90; p-value=0.74). However, patients who had been on lenalidomide for > 2 years experienced a significant benefit in OS compared with those on lenalidomide for ≤ 2 years (HR=0.36; p-value=0.0015), although no difference in PFS was observed between the two cohorts (HR=0.77; p-value=0.18). A similar trend in OS was seen for patients who had been on lenalidomide > 3 years compared with those on maintenance treatment ≤ 3 years, though not statistically significant (HR=0.47; p-value=0.10). Again, no difference in PFS was noted between the two groups. Lastly there were only 12 cases of SPM reported in all patients assessed with no statistically significant association to the duration of lenalidomide use. In all 12 cases, lenalidomide was suspended and the mortality among these patients was 50%. Conclusions: Maintenance lenalidomide improves response rates after auto HCT in some patients including the CR rate, however, the median time to achieve CR in these patients is approximately 13 months. The patients who received maintenance therapy for > 2years had a significantly lower risk of death with a trend of improved OS in patients who continued maintenance therapy beyond 3-years. We conclude that the maintenance therapy should be continued for at least 2 years and possibly longer after auto HCT. Table 1 Summary of Survival Outcomes Maintenance Treatment Initiation Measure Early (N=155) Late (N=184) p-value Progression-free survival Hazard ratio (95% CI)a 0.90 (0.63, 1.30) 0.57 Overall survival Hazard ratio (95% CI)a 0.90 (0.49, 1.66) 0.74 Duration of Maintenance Treatment Measure > 2 years (N=115) ≤ 2 years (N=224) p-value Progression-free survival Hazard ratio (95% CI)b 0.77 (0.52, 1.13) 0.18 Overall survival Hazard ratio (95% CI)b 0.36 (0.19, 0.67) 0.0015 > 3 years (N=49) ≤ 3 years (N=290) p-value Progression-free survival Hazard ratio (95% CI)b 0.75 (0.45, 1.26) 0.28 Overall survival Hazard ratio (95% CI)b 0.47 (0.19, 1.15) 0.10 a Cox proportional hazards regression model: measure included as a baseline covariate with the following additional covariates: patient’s cytogenetic risk, creatinine, hemoglobin, B2-microglobulin, ISS stage at diagnosis, disease status at auto HCT, and response prior to auto HCT. b Cox proportional hazards regression model: measure included as a time-dependent covariate with the covariates listed above. Figure 1 Comparison of Overall Survival in Early vs Late initiation of Revlimid Figure 1. Comparison of Overall Survival in Early vs Late initiation of Revlimid Figure 2 Overall Survival – All Patients Figure 2. Overall Survival – All Patients Disclosures Shah: Novartis: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Array: Consultancy, Research Funding. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Increased Disease Progression in HLA-a, -B, -C, -DRB1 and -DBP1 Matched Recipients of Unrelated Donor Transplants with Peripheral Blood Is Independent of Risk Groups By Disease Risk Index

Blood ◽

10.1182/blood.v126.23.2005.2005 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2005-2005

Author(s):

Betul Oran ◽

Rima M Saliba ◽

Yudith Carmazzi ◽

Elizabeth J. Shpall ◽

Katayoun Rezvani ◽

...

Keyword(s):

Disease Progression ◽

Peripheral Blood ◽

Disease Risk ◽

Risk Group ◽

Risk Index ◽

Risk Groups ◽

Study Cohort ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

The Impact

Abstract The use of unrelated donors matched in all alleles of HLA-A, -B, -C, and -DRB1 loci has been associated with superior outcomes compared with those having 1 or more mismatches. Recent studies showed increased transplant-related mortality (TRM) with the use of HLA-DPB1 mismatched donors supporting the notion that the ideal volunteer unrelated donor should fully match at HLA-A, -B, -C, and -DRB1 and lack -DPB1 mismatches. The issue of the effect of HLA-DPB1 mismatch on the disease progression rate is still controversial and we aimed to investigate the impact of HLA-DPB1 mismatch in the graft versus host direction on transplant outcomes in patients categorized according to the recently defined disease risk index (DRI) for disease risk classification. Our study cohort included 1,211 transplant patients with hematological malignancies whohave received an hematopoietic stem cell transplant (HSCT) from an unrelated HLA-A, -B, -C,-DRB1 matched donor by high resolution typing (8/8 matched) after 2005 through 2014. The study cohort had a median age of 55 (range, 19-77); the hematopoietic stem cell source was peripheral blood (PB) in 698 and bone marrow (BM) in 513 patients. Disease risk index (DRI) at HSCT was high or very high in 382 (33%), intermediate in 598 (51%), low in 185 (16%) patients. Of the pairs, 1,154 (95%) were matched atHLA-DQB1 and 1,116 (92%) at HLA- DRB3/4/5 by high resolution testing. However, 633 (52%) had mismatch at one of the DPB1 alleles and 208 (17%) had two mismatches. There was association between matching for DPB1and matching for DRB3/4/5 (p=0.002) but not with DQB1. In PB recipients, there was a highly significant decreaseof disease progression in DPB1 mismatched pairs (one and two allele; HR=0.7, p=0.01 and HR=0.6, p=0.01 respectively) as compared tothose pairs with DPB1 matched. The impact of mismatches at one or two alleles were not different on disease progression (HR=1.2, p=0.4). However, the impact of DPB1 mismatch on disease progression was not uniform in different disease risk groups by DRI. Mismatch at DPB1 significantly decreased disease progression only in the intermediate risk group (HR=0.5, p=0.002) but not in low risk and high/very high disease groups by DRI (HR=0.9, p=0.8 and HR=0.7, p=0.1 respectively) (Figure 1a-c). In BM recipients, increasing number of DPB1 incompatibilities decreased disease progression (HR=0.9, p=0.4 and HR=0.6, p=0.1 for 1 and 2 allele mismatches respectively) but did not reach significance. Mismatches at HLA-DQB1 and -DRB3/4/5 had no impact on disease progression in both PB and BM recipients. Pairs with one or two allele-level DPB1 mismatches increased TRM compared with DPB1 matched pairs in PB (HR=1.5, p=0.04 and HR=1.9, p=0.006 respectively) and BM recipients (HR=1.8, p=0.03 and HR=1.9, p=0.05). There was no difference between two and one allele DPB1 mismatched for TRM in PB and BM recipients. Multivariate analyses revealed that the negative impact of DPB1 mismatch on TRM was not uniform in younger or (?) older patients. Interestingly, DPB1 mismatches increased TRM only in younger (aged<55) patients (HR=2.3, p=0.02) if they were PB recipients but only in older patients (HR=2.03, p=0.046) if they were BM recipients. We next analyzed the impact of DPB1 matching on progression free survival (PFS) and did not observe any impact of DPB1 mismatches on PFS in PB (HR=0.9, p=0.9) and BM (HR=1.12, p=0.6) recipients. Subgroup analyses by DRI to identify a specific risk group that the use of HLA-A, -B, -C and -DRB1 matched but DPB1 mismatched unrelated donor might lead to improved PFS did not reveal any particular risk group in both PB and BM recipients. Thus, in recipients of HLA-A, -B-C and DRB1 allele-level matched unrelated donors a mismatch for DPB1 is associated with a significantlydecreased risk of disease progression with no impact on PFS in intermediate risk group by DRI. Further analysis permissive vs. non-permissive DPB1 mismatches would be warranted. Figure 1. The cumulative incidence of disease progression by DPB1 mismatch and Disease Risk Index in peripheral blood recipients. Figure 1. The cumulative incidence of disease progression by DPB1 mismatch and Disease Risk Index in peripheral blood recipients. Disclosures No relevant conflicts of interest to declare.

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