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
Authors: Armand Philippe , Kim Haesook T. , Logan Brent R. , Wang Zhiwei , Alyea Edwin P. , Kalaycio Matt , Maziarz Richard T. , Antin Joseph H. , Soiffer Robert J , Weisdorf Daniel J. , Rizzo J. Douglas , Horowitz Mary M. , Saber Wael 
Published: October 2019

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.