Abstract
T cell depletion by CD34+ cell selection of hematopoietic stem cell allografts ex vivo reduces the incidence and severity of GvHD, without increased risk of relapse in patients with acute leukemia in remission or MDS. The optimal candidate for CD34+-selected HCT remains unknown, however.
Objective:
To determine outcomes based on both disease- and patient-specific factors, we evaluated a prognostic model combining the Disease Risk Index (DRI) and Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), an approach recently shown to predicted overall survival in a broad population of allograft recipients (1).
Methods:
This was a retrospective analysis of 506 adult recipients of first allogeneic HCT with CD34+ selected PBSCs from 7/8- or 8/8-matched donors for AML (n = 290), ALL (n = 72), or MDS (n = 144). The Kaplan-Meier method estimated OS and RFS. The cumulative incidence method for competing risks estimated relapse and non-relapse mortality (NRM). We evaluated the univariate association between variables of interest and OS and RFS using the log-rank test. Cox regression models assessed the adjusted effect of covariates on OS/RFS.
Results:
Stratification of patients based on a composite of DRI (low/intermediate vs. high/very high) and HCT-CI (0–2 vs. ≥ 3) revealed differences in OS and RFS between the 4 groups. Compared with reference groups of patients with low/intermediate DRI and low or high HCT-CI, those with high DRI had a greater risk of death (HR 2.30; 95% CI 1.39, 3.81) and relapse or death (HR 2.50; 95% CI 1.55, 4.05) than patients with any HCT-CI but low/intermediate DRI (HR death 1.80; 95% CI 1.34, 2.43; HR relapse/death 1.68; 95% CI 1.26, 2.24).
Conclusions and Clinical Implications:
A model combining DRI and HCT-CI predicted survival after CD34+ cell–selected HCT. Application of this combined model to other cohorts, both in retrospective analyses and prospective trials, will enhance clinical decision making and patient selection for different transplant approaches.
Data Availability Statement:
The data that support the findings of this study are available on request from the corresponding author, C Cho. In order to protect the privacy of research participants, the data are not publicly available.
Keywords: Hematopoietic cell transplantation, allogeneic transplant, ex vivo manipulation
INTRODUCTION
For many patients with high-risk or relapsed/refractory hematologic malignancies, allogeneic hematologic cell transplantation (HCT) represents the only potential opportunity for cure. Risks of relapse and complications including graft-versus-host disease (GvHD), however, continue to pose significant barriers to improved long-term survival. For the transplant physician, devising a treatment plan that delivers maximal antileukemic benefit while minimizing the risk of nonrelapse mortality is a formidable challenge.
The combination of myeloablative conditioning (MAC) and T cell depletion (TCD) by CD34+ cell selection of hematopoietic stem cell allografts reduces the frequency and severity of GvHD, with no increased risk of relapse (2–7). At this time, however, the optimal candidate for CD34+-selected HCT is not known; nor is the upper limit of comorbidity burden or disease risk that can be allografted successfully with this approach. We have previously demonstrated that the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) (8) predicts nonrelapse mortality and overall survival after CD34+-selected peripheral blood stem cell transplantation (PBSCT) for myeloid malignancies (9). In addition to patient risk factors, disease features play a major role in posttransplant outcomes, and like the HCT-CI, the Disease Risk Index (DRI) (10) allows for risk stratification across heterogeneous transplant-specific populations. Kongtim et al. have recently combined these instruments to predict survival in large cohorts of HCT patients (1). Here we evaluate the DRI and explored the combined DRI/HCT-CI model in outcomes after CD34+-selected allogeneic PBSCT in adult patients with acute leukemia or MDS.
METHODS
Patient population
This retrospective analysis included adult recipients of first allogeneic HCTs with CD34+-selected PBSCTs from a 7/8- or 8/8-matched related or unrelated donor for acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) at Memorial Sloan Kettering Cancer Center between January 2000 and December 2015. High-resolution DNA-specific oligonucleotide typing characterized HLA-A, -B, -C, -DRB1, and - DQB1 loci. Clinical outcomes, including acute and chronic GvHD, relapse, and causes of death, were captured in real time per standard clinical practice. These data were retrieved from an institutional database and analyzed for this study. All patients and donors provided written informed consent for treatment. The MSKCC Institutional Review and Privacy Board approved this retrospective study.
Transplant procedures
All patients received myeloablative conditioning with one of the following regimens: (1) total body irradiation (TBI) 1 375 cGy in 11 fractions over 4 days, followed by thiotepa 5 mg/kg/day for 2 days and fludarabine 25 mg/m2/day for 5 days; (2) TBI 1,375 cGy followed by thiotepa 5 mg/kg/day for 2 days, then cyclophosphamide 60 mg/kg/day for 2 days; (3) intravenous busulfan 0.8 mg/kg/dose every 6 hours for 10 or 12 doses with first-dose pharmacokinetics to target a steady-state level of 600–900 ng/mL, melphalan 70 mg/m2/day for 2 doses, and fludarabine 25 mg/m2/day for 5 doses; or (4) clofarabine 20 mg/m2/day for 5 days, melphalan 70 mg/m2/day for 2 days, and thiotepa 5 mg/kg/day for 2 days (or 10 mg/kg for 1 day), all as previously described (11–14).
CD34+ stem cells initially underwent positive selection from granulocyte colony stimulating factor–mobilized PBSCs using the ISOLEX 300i Magnetic Cell Separator (Baxter, Deerfield, IL) followed by sheep RBC (sRBC) rosette depletion. Beginning in 2006 and exclusively after May 2010, allografts were processed using the CliniMACS CD34 Reagent System (Miltenyi Biotech, Gladbach, Germany). Patients received the allograft within 24–48 hours after completing cytoreduction. None received pharmacologic GvHD prophylaxis posttransplant. Graft rejection prophylaxis consisted of rabbit antithymocyte globulin (ATG) 2.5–10 mg/kg or equine ATG 30–45 mg/kg over 2–3 days. Patients received supportive care and opportunistic infection prophylaxis according to the institutional guidelines in place at the time of their transplant.
Study definitions and statistical analysis
Relapse was designated by standard guidelines (15–17). We assigned DRI scores in accordance with Armand et al. (10) and HCT-CI scores according to Sorror et al. (8). Cause of death was determined by the algorithm of Copelan et al. (18).
The Kaplan-Meier method estimated overall survival (OS) and relapse-free survival (RFS). The cumulative incidence method for competing risks estimated relapse and nonrelapse mortality (NRM). We evaluated the univariate association between variables of interest and OS and RFS using the log-rank test. Cox regression models assessed the adjusted effect of covariates on OS and RFS.
RESULTS
Patient and transplant characteristics
The analysis comprised a total of 506 patients. Patient and transplant characteristics are in Table 1. Among the 290 patients with AML, 214 (74%) were in first complete remission (CR), and 61 (21%) were in second CR. Similarly, of the 72 patients with ALL, 55 (76%) were in first CR, and the remaining 17 (24%) were in second CR. Of the patients with MDS, 43 (30%) underwent HCT for low-risk histologies (e.g. refractory anemia with ringed sideroblasts or refractory cytopenia with multilineage dysplasia), 98 (68%) for high-risk subtypes (refractory anemia with excess blasts or chronic myelomonocytic leukemia), and 3 (2%) for MDS/myeloproliferative neoplasm overlap syndromes. All MDS patients had < 10% marrow blasts pretransplant, and 128 (89%) had ≤ 5%. As only one patient of 506 had a very high DRI, we merged the high and very high groups for statistical analysis. Among the 434 patients with AML or MDS, 65 (15%) had therapy-related disease. Forty-three patients (9%) received maintenance therapy post-HCT, of whom 35 received azacytidine, 6 received tyrosine kinase inhibitors for Ph+ ALL, and 2 received sorafenib for FLT3-mutated disease.
Table 1.
Baseline patient and transplant characteristics.
| Characteristic | Value |
|---|---|
| Age, median (range), years | 55.4 (18.5–73.3) |
| Male sex, n (%) | 232 (46) |
| Disease, n (%) | |
| AML | 290 (57) |
| ALL | 72 (14) |
| MDS | 144 (28) |
| DRI, n (%) | |
| Low | 16 (3) |
| Intermediate | 420 (83) |
| High/very high | 70 (14) |
| HCT-CI, n (%) | |
| 0 | 97 (19) |
| 1–2 | 163 (32) |
| ≥ 3 (range 3–10) | 246 (49) |
| Combined DRI/HCT-CI, n (%) | |
| Low/intermediate DRI, HCT-CI 0–2 | 229 (45) |
| Low/intermediate DRI, HCT-CI ≥ 3 | 207 (41) |
| High/very high DRI, HCT-CI 0–2 | 31 (6) |
| High/very high DRI, HCT-CI ≥ 3 | 39 (8) |
| Donor type, n (%) | |
| 8/8-matched related | 187 (37) |
| 8/8-matched unrelated | 219 (43) |
| 7/8-matched | 100 (20) |
| Conditioning regimen, n (%) | |
| TBI/thiotepa/fludarabine | 77 (15) |
| TBI/thiotepa/cyclophosphamide | 109 (22) |
| Busulfan/melphalan/fludarabine | 308 (61) |
| Clofarabine/melphalan/thiotepa | 12 (2) |
| CD34+ cell selection method, n (%) | |
| ISOLEX 300i and sRBC | 228 (45) |
| CliniMACS | 278 (55) |
| CD34+ cell dose, median (range), cells/kg | 7.25 × 106 (0.01–87.7 × 106) |
| CD3+ cell dose, median (range), cells/kg | 2.0 × 103 (0.0–157.0 × 103) |
Survival
At the median follow-up of 56.2 months among survivors (range 8.1–180.0), 2-year estimated OS was 63.1% (95% confidence interval [CI] 58.7–67.2), and 5-year estimated OS was 53.7% (95% CI 49.0–58.2). Two-year estimated RFS was 58.2% (95% CI 53.8–62.4), and 5-year estimated RFS was 50.7% (95% CI 46.0–55.2).
DRI score was predictive of survival on univariate and multivariate analysis: Estimated 2-year OS was 100% in patients with low DRI, 64.9% (95% CI 60.1–69.3) in those with intermediate DRI, and 44.2% (95% CI 32.4–55.4) with high or very high DRI (p < 0.001; Figure 1A). RFS was also 100% at 2 years with low DRI but 60.4% (95% CI 55.5–65.0) with intermediate and 35.6% (95% CI 24.6–46.7) with high or very high DRI (p < 0.001; Figure 1B).
Figure 1.
DRI strongly predicts (A) overall survival and (B) relapse-free survival after CD34-selected allogeneic HCT. Univariate analysis demonstrated significantly differences in estimated 2-year OS (low: 100% [95% CI not applicable], intermediate: 64.9% [95% CI 60.1–69.3%], high/very high: 44.2% [95% CI 32.4–55.4%]), p < 0.001) and RFS (low: 100% [95% CI not applicable], intermediate: 60.4% [95% CI 55.5–65.0%], high/very high: 35.6% [95% CI 24.6–46.7%], p < 0.001). Given a very small number of patients with very high DRI, the high and very high DRI groups were merged.
HCT-CI and age also correlated with significant differences in OS and RFS (Table 2). Specifically, an HCT-CI score of 3 or higher corresponded to significantly worse OS (HR 1.87, 95% CI 1.27–2.74, p < 0.001) and RFS (HR 1.59, 95% CI 1.11–2.28, p = 0.002). Consistent with our prior report, OS and RFS did not differ significantly for patients with an HCT-CI score of 1–2 compared with those with a score of 0. Donor HLA match correlated with a significant difference in OS but not RFS. A diagnosis of ALL corresponded to significantly poorer RFS but not OS on uni- and multivariate analysis.
Table 2.
Results of univariate and multivariate analysis of factors associated with overall and relapse-free survival after CD34-selected allogeneic HCT.
| Univariate Analysis | Multivariate Analysis | |||||||
|---|---|---|---|---|---|---|---|---|
| Characteristic | 2 Year Estimated OS (95% CI) | p | 2 Year Estimated PFS (95% CI) | p | HR Death (95% CI) | p | HR Relapse or Death (95% CI) | p |
| Age | ||||||||
| < 55.4 years | 67.4% (61.1–72.8) | 0.03 | 62.6% (56.3–68.3) | 0.04 | Reference | 0.04 | Reference | 0.007 |
| ≥ 55.4 years | 58.9% (52.5–64.7) | 53.8% (47.5–59.8) | 1.33 (1.02–1.73) | 1.44 (1.10–1.88) | ||||
| DRI | ||||||||
| Low | 100% (NA) | < 0.001 | 100% (NA) | < 0.001 | Reference (combined low/intermediate) | < 0.001 | Reference (combined low/intermediate) | < 0.001 |
| Intermediate | 64.9% (60.1–69.3) | 60.4% (55.5–65.0) | ||||||
| High/very high | 44.2% (32.4–55.4) | 35.6% (24.6–46.7) | 2.03 (1.47–2.79) | 2.10 (1.53–2.88) | ||||
| HCT | ||||||||
| 0 | 79.1% (69.5–86.0) | < 0.001 | 68.7% (58.4–77.0) | < 0.001 | Reference | < 0.001 | Reference | 0.002 |
| 1–2 | 68.8% (61.0–75.4) | 65.9% (58.0–72.7) | 1.12 (0.73–1.72) | 1.00 (0.67–1.49) | ||||
| ≥ 3 | 53.0% (46.5–59.1) | 49.1% (42.6–55.2) | 1.87 (1.27–2.74) | 1.59 (1.11–2.28) | ||||
| Disease | ||||||||
| AML | 64.2% (58.4–69.4) | 0.06 | 58.1% (52.2–63.6) | 0.03 | Reference | 0.05 | ||
| ALL | 50.5% (38.3–61.5) | 47.7% (35.6–58.8) | 1.50 (1.05–2.14) | |||||
| MDS | 67.2% (58.7–74.3) | 63.7% (55.1–71.0) | 0.89 (0.84–0.94) | |||||
| Donor match | ||||||||
| 8/8 | 64.1% (59.2–68.6) | 0.02 | 59.3% (54.3–64.0) | 0.06 | Reference | 0.02 | ||
| 7/8 | 59.0% (48.7–67.9) | 53.9% (43.6–63.1) | 1.42 (1.05–1.91) | |||||
| Conditioning | ||||||||
| TBI | 62.4% (56.8–67.5) | 0.64 | 58.5% (52.8–63.7) | 0.93 | ||||
| Chemotherapy | 64.2% (56.9–70.7) | 57.8% (50.3–64.5) | ||||||
| T cell depletion method | ||||||||
| CliniMACS | 62.8% (56.7–68.3) | 0.44 | 58.3% (52.8–63.7) | 0.46 | ||||
| Isolex | 63.2% (56.5–69.0) | 57.9% (51.2–64.0) | ||||||
We subsequently stratified patients based on a composite of DRI and HCT-CI, resulting in 4 groups: (1) patients with low/intermediate DRI and HCT-CI 0–2 (n = 229 [45%]), (2) low/intermediate DRI and HCT-CI ≥ 3 (n = 207 [41%]), (3) high/very high DRI and HCT-CI 0–2 (n = 31 [6%]), and (4) high/very high DRI and HCT-CI ≥ 3 (n = 39 [8%]). Table 3 and Figure 2 illustrate differences in OS and RFS between the 4 four groups. In multivariate analysis controlling for age, donor HLA match, and disease (for RFS), compared with a reference group of patients with low/intermediate DRI and low HCT-CI, those with low/intermediate DRI but high HCT-CI were at significantly increased risk of poorer OS and RFS (OS: HR 1.80, 95% CI 1.34–2.43; RFS: HR 1.65, 95% CI 1.24–2.21). Those with high/very high DRI but low HCT-CI had still worse OS (HR 2.30, 95% CI 1.39–3.81) and RFS (HR 2.35, 95% CI 1.45–3.81). Patients with both high/very high DRI and high HCT-CI fared most poorly with respect to both OS (HR 3.42, 95% CI 2.24–5.24, p < 0.001) and RFS (HR 3.22, 95% CI 2.12–4.89, p < 0.001).
Table 3.
Results of univariate and multivariate analysis based on combined DRI/HCT-CI.
| Univariate Analysis | Multivariate Analysis | |||||||
|---|---|---|---|---|---|---|---|---|
| Characteristic | 2 Year Estimated OS (95% CI) | p | 2 Year Estimated RFS (95% CI) | p | HR Death (95% CI) | p | HR Relapse or Death (95% CI) | p |
| Age | ||||||||
| < 55.4 years | 67.4% (61.1–72.8) | 0.03 | 62.6% (56.3–68.3) | 0.04 | Reference | 0.04 | Reference | 0.007 |
| ≥ 55.4 years | 58.9% (52.5–64.7) | 53.8% (47.5–59.8) | 1.33 (1.02–1.73) | 1.44 (1.10–1.88) | ||||
| DRI and HCT-CI | ||||||||
| Low/Intermediate, 0–2 | 75.2% (69.0–80.3) | < 0.001 | Reference | < 0.001 | Reference | < 0.001 | ||
| Low/Intermediate, ≥ 3 | 56.3% (49.2–62.8) | 1.80 (1.34–2.43) | 1.65 (1.24–2.21) | |||||
| High/Very High, 0–2 | 54.6% (35.7–70.1) | 2.30 (1.39–3.81) | 2.35 (1.45–3.81) | |||||
| High/Very High, ≥ 3 | 35.9% (21.4–50.6) | 3.42 (2.24–5.24) | 3.22 (2.21–4.89) | |||||
| Disease | ||||||||
| AML | 64.2% (58.4–69.4) | 0.06 | 58.1% (52.2–63.6) | 0.03 | Reference | 0.05 | ||
| ALL | 50.5% (38.3–61.5) | 47.7% (35.6–58.8) | 1.50 (1.04–2.12) | |||||
| MDS | 67.2% (58.7–74.3) | 63.7% (55.1–71.0) | 0.89 (0.84–0.95) | |||||
| Donor match | ||||||||
| 8/8 | 64.1% (59.2–68.6) | 0.02 | 59.3% (54.3–64.0) | 0.06 | Reference | 0.02 | Reference | 0.10 |
| 7/8 | 59.0% (48.7–67.9) | 53.9% (43.6–63.1) | 1.42 (1.05–1.91) | 1.28 (0.96–1.72) | ||||
Figure 2.
A combined prognostic index integrating the DRI and HCT-CI predicts (A) overall survival and (B) relapse-free survival after CD34-selected allogeneic HCT. Stratification of patients based on DRI (low/intermediate vs. high/very high) and HCT-CI (0–2 vs. ≥ 3) gave rise to 4 groups with significantly different OS and RFS (Table 3).
Relapse and nonrelapse mortality
Cumulative incidence of relapse among all patients was 17.6% (95% CI 14.4–21.0) at 2 years and 20.8% (95% CI 17.2–24.6) at 5 years. DRI was significantly associated with increased risk of relapse, with cumulative incidence of 0.0% (95% CI NA) at both 2 and 5 years in patients with low DRI, 14.7% (95% CI 11.5–18.3) at 2 years and 18.0% (95% CI 14.3–22.0) at 5 years with intermediate DRI, and 38.6% (95% CI 27.2–49.9) at 2 years and 42.1% (95% CI 30.1–53.6) at 5 years with high or very high DRI (p < 0.001).
Cumulative incidence of NRM was 24.2% (95% CI 20.5–28.0) at 2 years and 28.5% (95% CI 24.4–32.7) at 5 years. HCT-CI corresponded to significantly increased risk of NRM, with cumulative incidence of 10.4% (95% CI 5.3–17.5) at 2 years and 11.6% (95% CI 6.1–18.9) at 5 years in patients with a score of 0, 19.8% (95% CI 14.1–26.3) at 2 years and 24.1% (95% CI 17.5–31.3) at 5 years with score 1–2, and 32.5% (95% CI 26.7–38.4) at 2 years and 38.1% (95% CI 31.7–44.5) at 5 years with score 3 or greater (p < 0.001). HLA match also associated with a significant difference in NRM, with a 2-year cumulative incidence of 22.0% (95% CI 18.1–26.2) and 5-year cumulative incidence of 25.1% (95% 20.8–29.6) among patients who received 8/8-matched allografts, contrasted with 2- and 5-year cumulative incidences of 33.0% (95% CI 24.0–42.3) and 40.9% (95% CI 31.0–50.6) in recipients of 7/8-matched grafts (p = 0.002).
Causes of death
The primary cause of death was relapse in 86 patients (37% of 230 total deaths), infection in 58 (25%), GvHD in 40 (17%), organ failure in 29 (13%), graft failure in 2 (1%), other malignancy in 5 (2%), and other or unknown cause in 10 (4%). Causes of death based on combined DRI/HCT-CI group are in figure 3. Thirty of the 39 patients with high DRI and HCT-CI score died. In this group, relapse was the cause of 53% of deaths (n = 16), followed by infection (n = 6, 20%), GvHD (n = 4, 13%), organ failure (n = 3, 10%), and graft rejection (n = 1, 3%).
Figure 3.
Distribution of major causes of death by combined DRI/HCT-CI group.
DISCUSSION
The DRI and HCT-CI are well-validated tools for risk stratification across large allogeneic transplant populations and have proved useful in the clinic and in the research setting. Kongtim et al. have shown that a prognostic model combining these tools predicted overall survival in a broad population of allograft recipients (1). Here, we demonstrate that such a model predicted survival after CD34+ cell–selected HCT.
DRI was a major determinant of outcome irrespective of HCT-CI in patients who underwent CD34+ cell–selected, T cell–depleted PBSCT for acute leukemia or MDS, despite myeloablative conditioning. Individuals with low DRI had outstanding outcomes in this cohort, with 100% 2-year OS and RFS. Given the extremely small number of patients in this group, it is unclear if these results are generalizable, but we can conclude that CD34+-selected HCT is a reasonable option for patients with low DRI. As expected, patients with low or intermediate DRI and low HCT-CI also fared well. The question will arise as to whether the use of T cell–replete allografts would provide superior disease control in patients with high DRI. Previous analyses have not demonstrated an increased risk of relapse with CD34+-selected HCT, but in addition to comparative retrospective analyses using this combined model, this question requires prospective evaluation. The randomized phase III BMT CTN 1301 trial (NCT 02345850), which compares CD34+ selection, unmodified HCT with post-transplant cyclophosphamide, and a control arm of unmodified HCT with standard immunosuppression in patients eligible for myeloablative conditioning (MAC), should shed light in this regard.
There are some key limitations of this analysis. The absence of data on minimal residual disease and expanded molecular profile in the current cohort forces us to omit important determinants of disease risk. Another limitation lies in the relatively homogeneous cohort, with the vast majority of patients transplanted for diseases with intermediate-risk DRI. Given the retrospective nature of this analysis, this may reflect biases in patient selection. The sample number of patients with high or very high DRI also likely contributed to fairly wide confidence intervals in statistical observations relating to those patients and thus diminished the ability to characterize differences between these and other groups; univariate estimates of survival among those with high/very high DRI and low-HCT-CI, for instance, appears potentially similar to those with low/intermediate DRI and high HCT-CI, at least in the first 2 years post-HCT. Formal validation of this model in a larger sample of CD34+-selected HCT recipients with longer follow-up is in progress.
This analysis confirmed our previous findings that, among recipients of CD34+-selected transplants, those with HCT-CI score of 1–2 had survival similar to those with a score of 0, indicating that this approach attenuates the risk of nonrelapse mortality in patients with intermediate HCT-CI (9). Strategies to reduce complications in patients with more substantial comorbidity burden, however, remain an unmet need. In the group of patients with both high/very high DRI and high HCT-CI, relapse and NRM contributed equally to mortality. Barring an ability to increase treatment intensity, we are, again, in need of effective targeted post-transplant therapies and other minimally toxic interventions to improve disease control. The randomized phase III BMT CTN 0901 trial, which compared RIC with MAC in patients with AML and MDS, was discontinued early due to increased rates of relapse with RIC (19), but this trial excluded patients older than age 65 or with HCT-CI score > 4. In practice, older and more comorbid patients are frequently referred for transplantation. Clarification of the optimal strategy for these patients and their likelihood of benefiting from allogeneic HCT is needed. In a recent retrospective analysis, we observed similar OS and RFS in patients older than 50 years who received RIC versus CD34+-selected PBSCT, while CD34+ selection was associated with improved chronic GvHD/relapse-free survival (CRFS) (20). We have also reported that NRM and survival in older recipients of CD34+-selected PBSCT were similar to those of younger patients transplanted with this approach (21, 22). These retrospective data suggest that CD34+ selection allows for the safe delivery of MAC to some patients in whom the combination of intensive conditioning and pharmacologic GvHD prophylaxis would otherwise be excessively toxic. This combined model would better estimate prognosis in these patients and identify precisely who stands to benefit most from CD34+ selection or an alternate approach. We encourage the adoption of such a model to optimize patient selection for various HCT approaches, assist the transplant physician in clinical decision making, and guide the design and interpretation of clinical trials.
CLINICAL IMPLICATIONS.
The Disease Risk Index and the Hematopoietic Cell Transplantation Comorbidity Index are well-validated tools for risk stratification across large transplant populations. This combined model incorporating the DRI and HCT-CI effectively stratified recipients of CD34+ cell–selected HCT into four prognostic groups. Application of this combined model to other cohorts, both in retrospective analyses and prospective studies, will enhance decision making and guide patient selection for different transplant approaches and clinical trials.
ACKNOWLEDGMENTS
Funding
This research was supported in part by National Institutes of Health award number P01 CA23766 and NIH/NCI Cancer Center Support Grant P30 CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
CONFLICTS OF INTEREST
SAG reports research support from Amgen, Actinium Pharmaceuticals, Celgene, Johnson & Johnson, Miltenyi Biotec, and Takeda Pharmaceutical Company; and serves on the scientific advisory boards of Amgen, Actinium Pharmaceuticals, Celgene, Johnson & Johnson, Jazz Pharmaceuticals, Takeda Pharmaceutical Company, Novartis, Kite Pharma, and Spectrum Pharmaceuticals. JUP reports research support and IP licensing from Seres Therapeutics and a research grant from Merck/Society for the Immunotherapy of Cancer. MRMV reports research support from Seres Therapeutics; and has consulted, received honoraria from or participated in advisory boards for Seres Therapeutics, Flagship Ventures, Novartis, Evela, Jass Pharmaceuticals, Therakos, Amgen, Merck, Acute Leukemia Forum, and DKMS Medical Council (Board); and has IP licensing with Seres Therapeutics and Juno Therapeutics. MAP reports honoraria from Abbvie, Bellicum, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, and Takeda; serves on DSMBs for Servier and Medigene and the scientific advisory boards of MolMed and NexImmune; and has received research support for clinical trials from Incyte and Miltenyi Biotec.
Footnotes
ETHICS STATEMENT
The authors confirm that the ethical policies of Advances in Cell and Gene Therapy, as noted on the journal’s author guidelines page, have been adhered to and the appropriate ethical review committee approval has been received. The study conformed to the US Federal Policy for the Protection of Human Subjects.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author, C Cho. In order to protect the privacy of research participants, the data are not publicly available.